Acylamino-substituted fused cyclopentanecarboxylic acid derivatives and their use as pharmaceuticals

ABSTRACT

The present invention relates to compounds of the formula I, 
     
       
         
         
             
             
         
       
     
     wherein A, Y, Z, R 3  to R 6 , R 20  to R 22  and R 50  have the meanings indicated in the claims, which are valuable pharmaceutical active compounds. Specifically, they are inhibitors of the endothelial differentiation gene receptor 2 (Edg-2, EDG2), which is activated by lysophosphatidic acid (LPA) and is also termed as LPA 1  receptor, and are useful for the treatment of diseases such as atherosclerosis, myocardial infarction and heart failure, for example. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use and pharmaceutical compositions comprising them.

This application is a Continuation of application Ser. No. 12/939,650,filed Nov. 4, 2010, which is a Continuation of International ApplicationNo. PCT/EP2009/002917, filed Apr. 22, 2009, which claims the benefit ofU.S. Application No. 61/117,336, filed Nov. 24, 2008, all of which areincorporated herein by reference in their entireties.

The present invention relates to compounds of the formula I,

wherein A, Y, Z, R³ to R⁶, R²⁰ to R²² and R⁶⁰ have the meaningsindicated below, which are valuable pharmaceutical active compounds.Specifically, they are inhibitors of the endothelial differentiationgene receptor 2 (Edg-2, EDG2), which is activated by lysophosphatidicacid (LPA) and is also termed as LPA₁ receptor, and are useful for thetreatment of diseases such as atherosclerosis, myocardial infarction andheart failure, for example. The invention furthermore relates toprocesses for the preparation of the compounds of the formula I, theiruse and pharmaceutical compositions comprising them.

LPA is a group of endogenous lysophospholipid derivatives including1-oleoyl-sn-glycerol 3-phosphate, for example. LPA activatesG-protein-coupled receptors (GPCR's) from the endothelialdifferentiation gene receptor family which belong to thelysophospholipid receptors. LPA signaling exerts a variety ofpleiotropic biological responses on many different cell types whichinterfere with processes such as cell proliferation, cell growth, cellhypertrophy, re-differentiation, cell retraction, cell contraction, cellmigration, cell survival or inflammation. The Edg receptor family,originally identified as a family of orphan GPCR's, currently compriseseight different members which were recently termed according to theirrespective ligand as LPA receptors or S1P receptors(sphingosine-1-phosphate receptors). According to the nomenclature ofthe International Union of Basic and Clinical Pharmacology (IUPHAR), LPAreceptors Edg-2, Edg-4 and Edg-7 are now also termed as LPA₁, LPA₂ andLPA₃ receptor (cf. I. Ishii et al., Annu. Rev. Biochem. 73 (2004),321-354).

LPA is generated mainly in the extracellular compartment by differentpathways predominantly by the cancer cell motility factor autotaxinwhich was recently found to be identical with lysophospholipase D. LPAcan also be generated by alternative routes involving phospholipasehydrolysis (PLA₁ and PLA₂) or other mechanisms such as de novophospholipid synthesis. Although LPA, in contrast to otherphospholipids, is highly soluble in water, in plasma it is carried bydifferent binding proteins such as albumin and gelsolin which display ahigh affinity to LPA and from which it can be released. Underpathophysiological conditions, levels of LPA can be elevated to anundesirable amount and thus increase LPA-mediated signaling and lead todetrimental processes such as abnormal cell proliferation, for example.Blocking LPA signaling, for example by Edg-2 inhibitors, allows toprevent such processes.

For example, increased liberation of LPA was observed during plateletactivation and blood clotting and at sites of inflammation (T. Sano et.al., J. Biol. Chem. 277 (2002), 21197-21206). After acute myocardialinfarction (AMI) in humans, LPA serum levels were significantly raisedin humans to about 6-fold higher concentrations, and LPA was regarded tobe involved in the pathophysiological processes in the cardiovascularsystem related to AMI (X. Chen et al., Scand. J. Clin. Lab. Invest. 63(2003), 497-503). The importance of LPA and its receptor Edg-2 for thepathophysiological processes after myocardial infarction such as cardiacremodeling and for the prevention of cardiac hypertrophy and heartfailure was confirmed in further investigations (J. Chen et al., J.Cell. Biochem. 103 (2008), 1718-1731). LPA was shown to be generatedduring mild oxidation of low density lipoprotein (LDL) particles and tobe accumulated in the lipid core of human atherosclerotic plaques (W.Siess et al., Proc. Natl. Acad. Sci. 96 (1999), 6931-6936). Furthermore,LPA was identified as an important bioactive component of moxLDL (mildlyoxidized low density lipoprotein) leading to platelet activation, and itwas shown that the effects of LPA, moxLDL or lipid core extracts fromhuman atherosclerotic plaques on platelet activation could be abrogatedby the Edg-2/Edg-7 receptor inhibitor dioctanoylglycerol pyrophosphateDGPP(8:0), implicating a causative role of LPA-mediated Edg receptorsignaling in platelet aggregation and usefulness of such LPA receptorinhibitors in the treatment of cardiovascular diseases (E. Rother etal., Circulation 108 (2003), 741-747).

Further findings underline the detrimental role of LPA during initiationand progression of cardiovascular diseases such as atherosclerosis, leftventricular remodeling and heart failure. LPA leads to pertussistoxin-sensitive, NFκB (nuclear factor kappa B)-mediated pro-inflammatoryresponses of endothelial cells including upregulation of chemokines likemonocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL8) (A.Palmetshofer et al., Thromb. Haemost. 82 (1999), 1532-1537) and exposureof endothelial cell adhesion molecules like E-selectin or intercellularadhesion molecule-1 (ICAM-1) (H. Lee et al., Am. J. Physiol. 287 (2004),C1657-C1666). Direct evidence for the involvement of Edg-2 receptorsarises from recent studies which demonstrate that LPA induces oxidativestress in vascular smooth muscle cells and endothelial cells which wasattenuated by pharmacological inhibition by DGPP(8:0) or THG1603, aspecific Edg-2 receptor antagonist (U. Kaneyuki et al., VascularPharmacology 46 (2007), 286-292; S. Brault et al., Am. J. Physiol.Regul. Integr. Comp. Physiol. 292 (2007), R1174-R1183). In vascularsmooth muscle cells, LPA leads to pertussis toxin-sensitive Ca²⁺ releasefrom internal stores, to activation of 42 kDa mitogen-activated proteinkinase (p42MAPK) and to cell proliferation (S. Seewald et al.,Atherosclerosis 130 (1997), 121-131). Intravascular injection of LPA wasshown to induce neointima formation in vivo (K. Yoshida et al.,Circulation 108 (2003), 1746-1752). On isolated adult cardiac myocytes,LPA leads to cellular hypertrophy and to activation of different kinasesknown to be relevant for a hypertrophic response (Y.-J. Xu et al.,Biochemical Pharmacology 59 (2000), 1163-1171). Studies on neonatalmyocytes confirmed a role of LPA in the induction of hypertrophy andrevealed the relevance of a rho kinase-dependent pathway (R.Hilal-Dandan et al., J. Mol. Cell. Cardiol. 36 (2004), 481-493). Therelevance of rho kinase underlines the involvement of the Edg-2receptors which, in contrast to Edg-7 receptors, are coupled toG_(α12/13) proteins. LPA furthermore attenuates the force of contractionin human myocardial ventricular and atrial preparations and impairsisoprenaline-induced fractional shortening of isolated adult ratventricular myocytes. The latter effects were reverted afterpre-incubation with pertussis toxin indicating the relevance of aGPCR-mediated and G_(αi/0)-mediated pathway (B. Cremers et al., J. Mol.Cell. Cardiol. 35 (2003), 71-80). LPA was also found to lead to enhancedmatrix generation and proliferation of cardiac fibroblasts (J. Chen etal., FEBS Letters 580 (2006), 4737-4745).

The importance of influencing Edg-2 receptor signaling and LPA-mediatedeffects for many diseases was confirmed by pharmacological approachesusing specific tool compounds or Edg-2 receptor knock-out mice or byexperimental silencing of the Edg-2 receptors. For example, therelevance of LPA-activated Edg receptors for renal diseases wasdemonstrated by different kinds of Edg-2/Edg-7 receptor inhibitors. Inone approach, it was shown that the LPA-induced proliferative responseof mesangial cells could be inhibited by the compound DGPP(8:0) (Y. Xinget al., Am. J. Physiol. Cell Physiol. 287 (2004), F1250-F1257). Inanother approach using the Edg-2/Edg-7 receptor inhibitor VPC12249 itwas demonstrated in an in vivo model of mouse renal ischemia reperfusionthat LPA displays a dual role in renoprotection. While Edg-4 receptorsignaling was shown to be beneficial, Edg-2 and Edg-7 receptor signalingaggravated renal injury, most probably due to enhanced infiltration ofleukocytes into the renal tissue, and should therefore be blocked fortreating or preventing ischemia/reperfusion-induced acute renal failure(M. D. Okusa et al., Am. J. Physiol. Renal Physiol. 285 (2003),F565-F574). The crucial role of Edg-2 receptors in the development oftubulointerstitial fibrosis was confirmed in a model of unilateralureteral obstruction (J. P. Pradere et al., J. Am. Soc. Nephrol. 18(2007), 3110-3118). In this model, renal injury was attenuated in Edg-2receptor knock-out mice or by pharmacological treatment with theEdg-2/Edg-7 receptor inhibitor Ki16425. The impact of the LPA/Edg-2receptor system in pulmonary fibrosis and vascular leakage was recentlyconfirmed by the finding that the bioactive content of LPA was increasedin bronchoalveolar fluid of humans suffering from idiopathic pulmonaryfibrosis. Edg-2 receptor knock-out mice were protected frombleomycin-induced lung injury and vascular leakage, as compared towild-type littermates (A. M. Tager et al., Nat. Med. 14 (2008), 45-54).

Direct involvement of Edg-2 receptors was recently demonstrated for theprogression of bone metastasis in vivo. Progression was reduced underpharmacological treatment with the Edg-2/Edg-7 receptor inhibitorKi16425 as well as after specific silencing of the Edg-2 receptors inthe same order of magnitude (A. Boucharaba et al., Proc. Natl. Acad.Sci. 103 (2006), 9643-9648). The relevance of Edg-2 receptors was alsoshown in vitro with respect to prostate cancer cell proliferation andmetastatic potential of human colon carcinoma cells (R. Guo et al.,Endocrinology 147 (2006), 4883-4892; D. Shida et al., Cancer Res. 63(2003), 1706-1711).

The relevance of LPA-mediated Edg-2 receptor signaling was alsodemonstrated in an in vivo model of neuropathic pain. Intrathecalinjection of LPA mimicked behavioral, morphological and biochemicalalterations similar to those observed after peripheral nerve injury.Non-redundant function of Edg-2 receptors was demonstrated in Edg-2receptor deficient mice which did not develop signs of neuropathic painafter nerve injury. Therefore, Edg-2 receptor signaling is regarded ascrucial in the initiation of neuropathic pain (M. Inoue et al., Nat.Med. 10 (2004), 712-718). Thus, it is evident that inhibition of theEdg-2 receptor and the effects of LPA by suitable inhibitors is anattractive approach for treating various diseases. Certain compoundswhich exhibit Edg-2 inhibitory activity, have already been described.For example, as compounds which are structurally related to LPA, theabove-mentioned compounds DGPP(8:0) or VPC12249 may be mentioned. In WO02/29001 and WO 2005/115150 amino compounds comprising a phosphategroup, phosphonate group or hydroxy group are described which haveactivity as agonists or antagonists of LPA receptors. LPA receptorantagonistic azole compounds which are characterized by a carbamategroup in the 4-position of the azole ring, are described in EP 1258484.The use of azole compounds, further heterocycles and other compounds formodulating the Edg-2, Edg-3, Edg-4 and Edg-7 receptor is described in WO03/062392. Compounds which have LPA receptor, especially Edg-2,antagonistic activity and which comprise a β-alanine moiety carrying abiphenyl-2-carbonyl group on the amino group, or an alcohol group and atleast three cyclic groups, are described in EP 1533294 and EP 1695955,respectively. But there still is a need for further Edg-2 inhibitorswhich exhibit a favorable property profile and can be used in thetreatment of diseases such as the above-mentioned ones and otherdiseases in which LPA signaling and Edg-2 receptors play a role. Thepresent invention satisfies this need by providing theacylamino-substituted fused cyclopentanecarboxylic acid derivatives ofthe formula I defined below.

Certain acylamino-substituted fused cyclopentanecarboxylic acidderivatives which structurally differ from the compounds of theinvention, have already been described, such as the compound2-benzoylamino-indane-2-carboxylic acid in R. Lohmar et al., Chem. Ber.113 (1980), 3706-3715. 2-Acylamino-indane-2-carboxylic acids which arecharacterized by an aryl or heteroaryl substituent on the benzene ringof the indane moiety and which control the function of the GPR34receptor and thereby inhibit histamine release, have been described inWO 2006/088246 (EP 1849465), among them the compounds of the formula Iin which the fused cyclopentane ring depicted in formula I together withring A is an indane ring which carries a 4-chlorophenyl substituent inthe 5-position, the groups R³ to R⁶ and R²⁰ are hydrogen, the group R⁶⁰is hydroxy or ethoxy and the cyclic residue containing the groups Y, Z,R²¹ and R²² is 4-(2-methyl-1H-benzoimidazol-1-ylmethyl)-phenyl, whichresidue may also be designated as4-(2-methyl-benzoimidazol-1-ylmethyl)-phenyl. The compounds of theformula I in which the fused cyclopentane ring depicted in formula Itogether with ring A is an unsubstituted indane ring, the groups R³ toR⁶ and R²⁰ are hydrogen, the group R⁶⁰ is hydroxy and the cyclic residuecontaining the groups Y, Z, R²¹ and R²² is6,2′,4′-trichlorobiphenyl-3-yl, 6-chloro-[1,1′,4′,1″]terphenyl-3-yl or4-chloro-3-(2-phenylethynyl)-phenyl, have been described in WO2006/044975 which relates to anti-tumor agents.

A subject of the present invention is a compound of the formula I, inany of its stereoisomeric forms or a mixture of stereoisomeric forms inany ratio, or a physiologically acceptable salt thereof, or aphysiologically acceptable solvate of any of them,

whereinring A is a 3-membered to 7-membered cycloalkane ring, a benzene ring,or a monocyclic 5-membered or 6-membered aromatic heterocyclic ringwhich comprises 1 or 2 identical or different hetero ring members chosenfrom the series consisting of N, N(R⁰), O and S, wherein the cycloalkanering is optionally substituted by one or more identical or differentsubstituents chosen from the series consisting of fluorine and(C₁-C₄)-alkyl, and the benzene ring and the heterocyclic rings areoptionally substituted by one or more identical or differentsubstituents chosen from the series consisting of halogen, R¹, HO—,R¹—O—, R¹—C(O)—O—, R¹—S(O)₂—O—, R¹—S(O)_(m)—, H₂N—, R¹—NH—, R¹—N(R¹)—,R¹—C(O)—NH—, R¹—C(O)—N(R⁷¹)—, R¹—S(O)₂—NH—, R¹—S(O)₂—N(R⁷¹)—, R¹—C(O)—,HO—C(O)—, R¹—CO(O)—, H₂N—C(O)—, R¹—NH—C(O)—, R¹—N(R¹)—C(O)—, H₂N—S(O)₂—,R¹—NH—S(O)₂—, R¹—N(R¹)—S(O)₂—, NC—, O₂N—, phenyl and Het;Y is chosen from the series consisting of N(R¹⁰), S, O, C(R¹²)═C(R¹³),N═C(R¹⁴) and C(R¹⁵)═N;Z is chosen from the series consisting of N and C(R¹⁶);R⁰ is chosen from the series consisting of hydrogen and R²;R¹, R², R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸ are, independently ofeach other group R¹, R², R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸,chosen from the series consisting of (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl- which are all optionally substitutedby one or more identical or different substituents R⁷⁰;R³ and R⁵ are independently of each other chosen from the seriesconsisting of hydrogen, (C₁-C₄)-alkyl, phenyl-(C₁-C₄)-alkyl-, phenyl andhydroxy;R⁴ and R⁶ are independently of each other chosen from the seriesconsisting of hydrogen and (C₁-C₄)-alkyl;R¹⁰ is chosen from the series consisting of hydrogen and R¹¹;R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently of each other chosen fromthe series consisting of hydrogen, halogen, (C₁-C₄)-alkyl,(C₁-C₄)-alkyl-S(O)_(m)—, H₂N—, (C₁-C₄)-alkyl-NH—, (C₁-C₄)-alkyl-C(O)—,NC— and O₂N—;R²⁰ is chosen from the series consisting of hydrogen and (C₁-C₄)-alkyl;one of the groups R²¹ and R²² is a group of the formula II

R²⁴—R²³—  II

and the other of the groups R²¹ and R²² is chosen from the seriesconsisting of hydrogen, halogen, R³⁰, HO—, R³⁰—O—, R³⁰—C(O)—O—,R³⁰—S(O)₂—O—, R³⁰—S(O)_(m)—, H₂N—, R³⁰—NH—, R³⁰—N(R³⁰)—, R³⁰—C(O)—NH—,R³⁰—C(O)—N(R⁷¹)—, R³⁰—S(O)₂—NH—, R³⁰—S(O)₂—N(R⁷¹)—, R³⁰—C(O)—, HO—C(O)—,R³⁰—O—C(O)—, H₂N—C(O)—, R³⁰—NH—C(O)—, R³⁰—N(R³⁰)—C(O)—, H₂N—S(O)₂—,R³⁰—NH—S(O)₂—, R³⁰—N(R³⁰)—S(O)₂—, NC—, O₂N— and Het¹;R²³ is a direct bond or a chain consisting of 1 to 5 chain members ofwhich 0, 1 or 2 chain members are identical or different hetero chainmembers chosen from the series consisting of N(R²⁵), O, S, S(O) andS(O)₂, but two hetero chain members can be present in adjacent positionsonly if one of them is chosen from the series consisting of S(O) andS(O)₂ and the other is chosen from the series consisting of N(R²⁵), Oand S, and the other chain members are identical or different groupsC(R²⁶)(R²⁶), wherein two adjacent groups C(R²⁶)(R²⁶) can be connected toeach other by a double bond or a triple bond;R²⁴ is chosen from the series consisting of hydrogen, R³¹, HO—, R³¹—O—,R³¹—C(O)—O—, R³¹—S(O)_(m)—, H₂N—, R³¹—NH—, R³¹—N(R³¹)—, R³¹—C(O)—NH—,R³¹—C(O)—N(R⁷¹)—, R³¹—S(O)₂—NH—, R³¹—S(O)₂—N(R⁷¹)—, R³¹—C(O)—, HO—C(O)—,R³¹—O—C(O)—, H₂N—C(O)—, R³¹—NH—C(O)—, R³¹—N(R³¹)—C(O)—, H₂N—S(O)₂—,R³¹—NH—S(O)₂—, R³¹—N(R³¹)—S(O)₂—, NC— and a 3-membered to 10-membered,monocyclic, bicyclic or tricyclic ring which is saturated or unsaturatedand contains 0, 1, 2 or 3 identical or different hetero ring memberschosen from the series consisting of N,N(R³²), O, S, S(O) and S(O)₂,which ring is optionally substituted on ring carbon atoms by one or moreidentical or different substituents chosen from the series consisting ofhalogen, R³³, HO—, R³³—O—, R³³—C(O)—O—, R³³—S(O)₂—O—, R³³—S(O)_(m)—,H₂N—, R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—, R³³—C(O)—N(R⁷¹)—,R³³—S(O)₂—NH—, R³³—S(O)₂—N(R⁷¹)—, H₂N—S(O)₂—NH—, R³³—NH—S(O)₂—NH—,R³³—N(R³³)—S(O)₂—NH—, H₂N—S(O)₂—N(R⁷¹)—, R³³—NH—S(O)₂—N(R⁷¹)—,R³³—N(R³³)—S(O)₂—N(R⁷¹)—, R³³—C(O)—, HO—C(O)—, R³³—O—C(O)—, H₂N—C(O)—,R³³—NH—C(O)—, R³³—N(R³³)—C(O)—, H₂N—S(O)₂—, R³³—NH—S(O)₂—,R³³—N(R³³)—S(O)₂—, NC—, O₂N—, oxo, phenyl and Het,provided that the total number of C, N, O and S atoms which is presentin the two groups R²³ and R²⁴, is at least 5;R²⁵ is chosen from the series consisting of hydrogen and (C₁-C₄)-alkyl;R²⁶, independently of each other group R²⁶, is chosen from the seriesconsisting of hydrogen, fluorine, (C₁-C₄)-alkyl and HO—, or two groupsR²⁶ bonded to the same carbon atom together are oxo, or two of thegroups R²⁶ or one group R²⁵ and one group R²⁶, together with thecomprised chain members, form a 3-membered to 7-membered monocyclic ringwhich is saturated and contains 0, 1 or 2 identical or different heteroring members chosen from the series consisting of N,N(R³⁴), O, S, S(O)and S(O)₂, which ring is optionally substituted on ring carbon atoms byone more identical or different substituents chosen from the seriesconsisting of fluorine and (C₁-C₄)-alkyl;R³¹ is chosen from the series consisting of (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl and (C₂-C₆)-alkynyl which are all optionally substitutedby one or more identical or different substituents R⁷⁰;R³² and R³⁴ are independently of each other chosen from the seriesconsisting of hydrogen, R³⁵, R³⁵—S(O)₂—, R³⁵—C(O)—, R³⁵—O—C(O)—, phenyland Het;R⁵⁰ is chosen from the series consisting of R⁵¹—O— and R⁵²—N(R⁵³)—;R⁵¹ is chosen from the series consisting of hydrogen and R⁵⁴;R⁵² is chosen from the series consisting of hydrogen, R⁵⁵, NC— andR⁵⁶—S(O)₂—;R⁵³ is chosen from the series consisting of hydrogen and R⁵⁷;R⁵⁶ is chosen from the series consisting of R⁵⁸ and phenyl;R⁶⁰, independently of each other group R⁶⁰, is chosen from the seriesconsisting of hydrogen and (C₁-C₄)-alkyl;R⁷⁰ is chosen from the series consisting of HO—, R⁷¹—O—, R⁷¹—C(O)—O—,R⁷¹—S(O)_(m)—, H₂N—, R⁷¹—NH—, R⁷¹—N(R⁷¹)—, R⁷¹—C(O)—NH—,R⁷¹—C(O)—N(R⁷¹)—, R⁷¹—S(O)₂—NH—, R⁷¹—S(O)₂—N(R⁷¹)—, HO—C(O)—,R⁷¹—O—C(O)—, H₂N—C(O)—, R⁷¹—NH—C(O)—, R⁷¹—N(R¹⁷)—C(O)—, H₂N—S(O)₂—,R⁷¹—NH—S(O)₂—, R⁷¹—N(R⁷¹)—S(O)₂—, NC—, oxo, phenyl and Het²;R⁷¹, independently of each other group R⁷¹, is chosen from(C₁-C₄)-alkyl, (C₃-C₄)-cycloalkyl and (C₃-C₄)-cycloalkyl-(C₁-C₂)-alkyl-;Het, independently of each other group Het, is a monocyclic 4-memberedto 7-membered heterocyclic ring which comprises 1, 2 or 3 identical ordifferent hetero ring members chosen from the series consisting ofN,N(R⁶⁰), O, S, S(O) and S(O)₂, which ring is saturated or unsaturatedand is optionally substituted by one or more identical or differentsubstituents chosen from the series consisting of halogen, (C₁-C₄)-alkyland R⁷⁰;Het¹ is a monocyclic 4-membered to 7-membered heterocyclic ring whichcomprises 1 or 2 identical or different hetero ring members chosen fromthe series consisting of N,N(R⁶⁰), O, S, S(O) and S(O)₂, which ring issaturated and is optionally substituted by one or more identical ordifferent substituents chosen from the series consisting of fluorine and(C₁-C₄)-alkyl;Het² is a monocyclic 5-membered or 6-membered heterocyclic ring whichcomprises 1, 2 or 3 identical or different hetero ring members chosenfrom the series consisting of N,N(R⁶⁰), O and S, which ring is aromaticand is optionally substituted by one or more identical or differentsubstituents chosen from the series consisting of halogen,(C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and NC—;m, independently of each other number m, is an integer chosen from theseries consisting of 0, 1 and 2;phenyl, independently of each other group phenyl, is optionallysubstituted by one or more identical or different substituents chosenfrom the series consisting of halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—and NC—, unless specified otherwise;cycloalkyl, independently of each other group cycloalkyl, andindependently of any other substituents on cycloalkyl, is optionallysubstituted by one or more identical or different substituents chosenfrom fluorine and (C₁-C₄)-alkyl;alkyl, alkenyl and alkynyl, independently of each other group alkyl,alkenyl and alkynyl, and independently of any other substituents onalkyl, alkenyl and alkynyl, is optionally substituted by one or morefluorine substituents;provided that the compound of the formula I is not2-[(6,2′,4′-trichlorobiphenyl-3-carbonyl)amino]indane-2-carboxylic acid,2-[6-chloro-[1,1′,4′,1″]terphenyl-3-carbonyl)amino]indane-2-carboxylicacid, 2-(4-chloro-3-phenylethynyl-benzoylamino)-indane-2-carboxylicacid,5-(4-chloro-phenyl)-2-[4-(2-methyl-1H-benzoimidazol-1-ylmethyl)-benzoylamino]-indane-2-carboxylicacid or5-(4-chloro-phenyl)-2-[4-(2-methyl-1H-benzoimidazol-1-ylmethyl)-benzoylamino]-indane-2-carboxylicacid ethyl ester.

If structural elements such as groups, substituents or numbers, forexample, can occur several times in the compounds of the formula I, theyare all independent of each other and can in each case have any of theindicated meanings, and they can in each case be identical to ordifferent from any other such element. In a dialkylamino group, forexample, the alkyl groups can be identical or different.

Alkyl groups, i.e. saturated hydrocarbon residues, can be linear(straight-chain) or branched. This also applies if these groups aresubstituted or are part of another group, for example an alkyl-O— group(alkyloxy group, alkoxy group) or an HO-substituted alkyl group(hydroxyalkyl group). Depending on the respective definition, the numberof carbon atoms in an alkyl group can be 1, 2, 3, 4, 5 or 6, or 1, 2, 3or 4, or 1, 2 or 3, or 1 or 2, or 1. Examples of alkyl are methyl,ethyl, propyl including n-propyl and isopropyl, butyl including n-butyl,sec-butyl, isobutyl and tert-butyl, pentyl including n-pentyl,1-methylbutyl, isopentyl, neopentyl and tert-pentyl, and hexyl includingn-hexyl, 3,3-dimethylbutyl and isohexyl. Examples of alkyl-O— groups aremethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, n-pentoxy. Examples of alkyl-S(O)_(m)— are methylsulfanyl-(CH₃—S—), methanesulfinyl- (CH₃—S(O)—), methanesulfonyl (CH₃—S(O)₂—),ethylsulfanyl- (CH₃—CH₂—S—), ethanesulfinyl-(CH₃—CH₂—S(O)—),ethanesulfonyl (CH₃—CH₂—S(O)₂—), 1-methylethylsulfanyl-((CH₃)₂CH—S—),1-methylethanesulfinyl- ((CH₃)₂CH—S(O)—), 1-methylethanesulfonyl((CH₃)₂CH—S(O)₂—). In one embodiment of the invention the number m ischosen from 0 and 2, wherein all numbers m are independent of each otherand can be identical or different. In another embodiment the number m inany of its occurrences is, independent of its meaning in otheroccurrences, 0. In another embodiment the number m in any of itsoccurrences is, independent of its meaning in other occurrences, 2.

A substituted alkyl group can be substituted in any positions, providedthat the respective compound is sufficiently stable and is suitable as apharmaceutical active compound. The prerequisite that a specific groupand a compound of the formula I are sufficiently stable and suitable asa pharmaceutical active compound, applies in general with respect to thedefinitions of all groups in the compounds of the formula I. An alkylgroup which is optionally substituted by one or more fluorinesubstituents can be unsubstituted, i.e. not carry fluorine substituents,or substituted, for example by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11fluorine substituents, or by 1, 2, 3, 4 or 5 fluorine substituents,which can be located in any positions. For example, in afluoro-substituted alkyl group one or more methyl groups can carry threefluorine substituents each and be present as trifluoromethyl groups,and/or one or more methylene groups (CH₂) can carry two fluorinesubstituents each and be present as difluoromethylene groups. Theexplanations with respect to the substitution of a group by fluorinealso apply if the group additionally carries other substituents and/oris part of another group, for example of an alkyl-O— group. Examples offluoro-substituted alkyl groups are trifluoromethyl, 2-fluoroethyl,1-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl,4,4,4-trifluorobutyl and heptafluoroisopropyl. Examples offluoro-substituted alkyl-O— groups are trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy and 3,3,3-trifluoropropoxy.Examples of fluoro-substituted alkyl-S(O)_(m)— groups aretrifluoromethylsulfanyl- (CF₃—S—), trifluoromethanesulfinyl-(CF₃—S(O)—)and trifluoromethanesulfonyl (CF₃—S(O)₂—).

The above explanations with respect to alkyl groups applycorrespondingly to unsaturated hydrocarbon residues, i.e. alkenylgroups, which in one embodiment of the invention contain one doublebond, and alkynyl groups, which in one embodiment of the inventioncontain one triple bond. Thus, for example, alkenyl groups and alkynylgroups can likewise be linear or branched, and substituted alkenyl andalkynyl groups can be substituted in any positions, provided that theresulting compound is sufficiently stable and is suitable as apharmaceutical active compound. Double bonds and triple bonds can bepresent in any positions. The number of carbon atoms in an alkenyl oralkynyl group can be 2, 3, 4, 5 or 6, for example 2, 3, 4 or 5. Examplesof alkenyl and alkynyl are ethenyl (vinyl), prop-1-enyl, prop-2-enyl(allyl), but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl,hex-3-enyl, hex-4-enyl, 4-methylhex-4-enyl, prop-1-ynyl, prop-2-ynyl(propargyl), but-2-ynyl, but-3-ynyl, 4-methylpent-2-ynyl, hex-4-ynyl andhex-5-ynyl. In one embodiment of the invention, an alkenyl or alkynylgroup contains at least three carbon atoms and is bonded to theremainder of the molecule via a carbon atom which is not part of adouble bond or triple bond.

The above explanations with respect to alkyl groups applycorrespondingly to alkanediyl groups (divalent alkyl groups) includingchains of one or more groups C(R²⁶)(R²⁶) which latter groups as such andchains of such groups are alkanediyl groups in case R²⁶ is chosen fromhydrogen and (C₁-C₄)-alkyl, or are substituted alkanediyl groups in caseany of the groups R²⁶ has a meaning different from hydrogen and(C₁-C₄)-alkyl. Likewise, the alkyl part of a substituted alkyl group canalso be regarded as an alkanediyl group. Thus, alkanediyl groups canalso be linear or branched, the bonds to the adjacent groups can belocated in any positions and can start from the same carbon atom or fromdifferent carbon atoms, and they can be substituted by fluorinesubstituents. Examples of alkanediyl groups are —CH₂—, —CH₂—CH₂—,—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—CH₂—, —CH(CH₃)—,—C(CH₃)₂—, —CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—, —C(CH₃)₂—CH₂—, —CH₂—C(CH₃)₂—.Examples of fluoro-substituted alkanediyl groups, which can contain 1 2,3, 4, 5 or 6 fluorine substituents, for example, are —CHF—, —CF₂—,—CF₂—CH₂—, —CH₂—CF₂—, —CF₂—CF₂—, —CF(CH₃)—, —C(CF₃)₂—,—C(CH₃)₂—CF₂₋₃—CF₂—C(CH₃)₂—. Further, the above explanations applycorrespondingly to divalent residues of unsaturated hydrocarbons, i.e.unsaturated alkanediyl groups such as alkenediyl groups and alkynediylgroups, which groups can occur in the group R²³ in case two adjacentgroups C(R²⁶)(R²⁶) are connected to each other by a double bond ortriple bond and which groups in one embodiment of the invention containone double bond or one triple bond, respectively, which can be presentin any positions, and which groups are optionally substituted byfluorine substituents. Examples of such unsaturated divalent groups are—CH═CH—, —CH₂—CH═CH—, —CH═CH—CH₂—, —CH₂—CH═CH—CH₂—, —C≡C—, —CH₂—C≡C—,—C≡C—CH₂—, —C(CH₃)₂—C≡C—, —C≡C—C(CH₃)₂—, —CH₂—C≡C—CH₂—.

The number of ring carbon atoms in a (C₃-C₇)-cycloalkyl group can be 3,4, 5, 6 or 7. Examples of cycloalkyl are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl groups which areoptionally substituted by one or more (C—O₄)-alkyl substituents, can beunsubstituted, i.e. not carry alkyl substituents, or substituted, forexample by 1, 2, 3 or 4 identical or different (C₁-C₄)-alkylsubstituents, for example by methyl groups, which substituents can belocated in any positions.

Examples of such alkyl-substituted cycloalkyl groups are1-methylcyclopropyl, 2,2-dimethylcyclopropyl, 1-methylcyclopentyl,2,3-dimethylcyclopentyl, 1-methylcyclohexyl, 4-methylcyclohexyl,4-isopropylcyclohexyl, 4-tert-butylcyclohexyl and3,3,5,5-tetramethylcyclohexyl. Cycloalkyl groups which are optionallysubstituted by one or more fluorine substituents, can be unsubstituted,i.e. not carry fluorine substituents, or substituted, for example by 1,2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 fluorine substituents, or by 1, 2, 3,4, 5 or 6 fluorine substituents. The fluorine substituents can belocated in any positions of the cycloalkyl group and can also be locatedin an alkyl substituent on the cycloalkyl group. Examples offluoro-substituted cycloalkyl groups are 1-fluorocyclopropyl,2,2-difluorocyclopropyl, 3,3-difluorocyclobutyl, 1-fluorocyclohexyl,4,4-difluorocyclohexyl and 3,3,4,4,5,5-hexafluorocyclohexyl. Cycloalkylgroups can also be substituted simultaneously by fluorine and alkyl.Examples of the group (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl- arecyclopropylmethyl-, cyclobutylmethyl-, cyclopentylmethyl-,cyclohexylmethyl-, cycloheptylmethyl-, 1-cyclopropylethyl-,2-cyclopropylethyl-, 1-cyclobutylethyl-, 2-cyclobutylethyl-,1-cyclopentylethyl-, 2-cyclopentylethyl-, 1-cyclohexylethyl-,2-cyclohexylethyl-, 1-cycloheptylethyl-, 2-cycloheptylethyl-. Theexplanations with respect cycloalkyl groups apply correspondingly tounsaturated cycloalkyl groups such as cycloalkenyl groups which canoccur in the group R²⁴ and which in one embodiment of the inventioncontain one double bond which can be present in any positions, anddivalent cycloalkyl groups (cycloalkanediyl groups), which latter groupscan occur in case two of the groups R²⁶ together with the comprisedchain members form a ring. Likewise, the cycloalkyl part of asubstituted cycloalkyl group can also be regarded as a cycloalkanediylgroup. Thus, for example, the bonds through which a cycloalkanediylgroup, such as a ring formed by two of the groups R²⁶ together with thecomprised chain members, is connected to the adjacent groups, can belocated in any positions and can start from the same ring carbon atom orfrom different ring carbon atoms.

In substituted phenyl groups, including phenyl groups which representthe 3-membered to 10-membered, monocyclic, bicyclic or tricyclic ringrepresenting R²⁴, the substituents can be located in any positions. Inmonosubstituted phenyl groups, the substituent can be located in the2-position, the 3-position or the 4-position. In disubstituted phenylgroups, the substituents can be located in 2,3-position, 2,4-position,2,5-position, 2,6-position, 3,4-position or 3,5-position. Intrisubstituted phenyl groups, the substituents can be located in2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position,2,4,6-position or 3,4,5-position. If a phenyl group carries foursubstituents, some of which can be fluorine atoms, for example, thesubstituents can be located in 2,3,4,5-position, the 2,3,4,6-position or2,3,5,6-position. If a polysubstituted phenyl group or any otherpolysubstituted group such as a heteroaryl group carries differentsubstituents, each substituent can be located in any suitable position,and the present invention comprises all positional isomers. The numberof substituents in a substituted phenyl group can be 1, 2, 3, 4 or 5. Inone embodiment of the invention, a substituted phenyl group, andlikewise another substituted group such as a heteroaryl group, carries1, 2 or 3, for example 1 or 2, identical or different substituents.

In heterocyclic groups, including the groups Het, Het¹ and Het² andheterocyclic rings which can be present in structural elements in thecompounds of the formula I such as the ring A or the 3-membered to10-membered ring representing R²⁴ or a ring formed by a group R²⁵ and agroup R²⁶ together with the comprised chain members, for example, thehetero ring members specified in the respective definition can bepresent in any combination and located in any suitable ring positions,provided that the resulting group and the compound of the formula I aresufficiently stable and suitable as a pharmaceutical active compound. Inone embodiment of the invention two oxygen atoms in any heterocyclicring in the compounds of the formula I cannot be present in adjacentring positions. In another embodiment two hetero ring members from theseries consisting of O, S and N atoms carrying a hydrogen atom or asubstituent, cannot be present in adjacent ring positions. Examples ofsuch series are the hetero ring members O, S and N(R³²), or O, S andN(R³⁴), or O, S and N(R⁶⁰). In another embodiment of the invention twohetero ring members from the series consisting of S(O) and S(O)₂ cannotbe present in adjacent ring positions. In an aromatic heterocyclic ringthe choice of hetero ring members and their positions is limited by theprerequisite that the ring is aromatic, i.e. it comprises a cyclicsystem of six delocalized pi electrons. The residue of a monocyclic,5-membered or 6-membered, aromatic heterocyclic ring, which can occur inthe groups Het, Het² and the 3-membered to 10 membered ring representingR²⁴, for example, can also be designated as monocyclic, 5-membered or6-membered heteroaryl group. The ring nitrogen atom in such a heteroarylgroup which carries the group R³² or R⁶⁰, respectively, is the ringnitrogen atom in a 5-membered ring such as pyrrole, pyrazole, imidazoleor triazole to which an exocyclic atom or group such as a hydrogen atomis bonded, and can be present once only in a 5-membered aromatic ringjust as the hetero ring members O and S. Examples of rings from whichsuch a heteroaryl group can be derived are pyrrole, furan, thiophene,imidazole, pyrazole, triazoles including [1,2,3]triazole and[1,2,4]triazole, oxazole ([1,3]oxazole), isoxazole ([1,2]oxazole),thiazole ([1,3]thiazole), isothiazole ([1,2]thiazole), oxadiazolesincluding [1,2,4]oxadiazole, [1,3,4]oxadiazole and [1,2,5]oxadiazole,thiadiazoles including [1,3,4]thiadiazole, pyridine, pyridazine,pyrimidine, pyrazine, triazines including [1,2,3]triazine,[1,2,4]triazine and [1,3,5]triazine. These explanations with respect tomonocyclic, 5-membered or 6-membered heteroaryl groups applycorrespondingly to the monocyclic, 5-membered or 6-membered, aromaticheterocyclic ring representing the ring A in formula I in which the ringnitrogen atom carrying the group R⁰ can likewise be present once only ina 5-membered ring such as pyrrole, pyrazole or imidazole. Just so, thehetero ring members O and S can be present once only in the ring A. Inone embodiment of the invention, a monocyclic, 5-membered or 6-memberedheteroaryl group comprises one or two identical or different hetero ringmembers, in another embodiment of the invention such a heteroaryl groupcomprises one hetero ring member, which are defined as indicated, and inanother embodiment of the invention such a heteroaryl is chosen fromthiophenyl, thiazolyl and pyridinyl. A monocyclic, 5-membered or6-membered heteroaryl group can be bonded via any ring carbon atom or,in the case of a 5-membered ring comprising a hetero ring member N(R³²)or N(R⁶⁰), via a ring nitrogen atom, wherein in the latter case the bondvia which the heteroaryl group is attached to the remainder of themolecule, replaces the group R³² or R⁶⁰. In one embodiment of theinvention, a monocyclic, 5-membered or 6-membered heteroaryl group isbonded via a ring carbon atom. For example, a thiophenyl group (thienylgroup) can be thiophen-2-yl (2-thienyl) or thiophen-3-yl (3-thienyl),furanyl can be furan-2-yl or furan-3-yl, pyridinyl (pyridyl) can bepyridin-2-yl, pyridin-3-yl or pyridin-4-yl, pyrazolyl can be1H-pyrazol-3-yl, 1H-pyrazol-4-yl or 2H-pyrazol-3-yl, imidazolyl can be1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl or3H-imidazolyl-4-yl, thiazolyl can be thiazol-2-yl, thiazol-4-yl orthiazol-5-yl.

In substituted monocyclic, 5-membered or 6-membered heteroaryl groups,the substituents can be located in any positions, for example in athiophen-2-yl group or a furan-2-yl group in the 3-position and/or inthe 4-position and/or in the 5-position, in a thiophen-3-yl group or afuran-3-yl group in the 2-position and/or in the 4-position and/or inthe 5-position, in a pyridin-2-yl group in the 3-position and/or in the4-position and/or in the 5-position and/or in the 6-position, in apyridin-3-yl group in the 2-position and/or in the 4-position and/or inthe 5-position and/or in the 6-position, in a pyridin-4-yl group in the2-position and/or in the 3-position and/or in the 5-position and/or inthe 6-position. In one embodiment of the invention, a substitutedmonocyclic, 5-membered or 6-membered heteroaryl group is substituted by1, 2 or 3, for example 1 or 2, identical or different substituents.Generally, besides optionally carrying the substituents indicated in thedefinition of the group, suitable ring nitrogen atoms in a monocyclic,5-membered or 6-membered heteroaryl group as well as in otherheterocyclic groups, for example in a 3-membered to 10-membered,monocyclic, bicyclic or tricyclic ring representing R²⁴ or in thearomatic ring A or the aromatic ring comprising the groups Y and Z whichare depicted in formula I, for example the nitrogen atom in a pyridinylgroup or a nitrogen atom in a [1,2,5]oxadiazolyl group, can also carryan oxido substituent —O⁻ and be present as an N-oxide.

The above explanations with respect to monocyclic, 5-membered or6-membered aromatic heterocyclic groups apply correspondingly to thebicyclic aromatic heterocyclic groups discussed below which can occur inthe 3-membered to 10-membered ring representing R²⁴ and which can alsobe designated as a bicyclic heteroaryl group.

Besides monocyclic, 5-membered or 6-membered, aromatic heterocyclicgroups, the group Het comprises monocyclic, 4-membered to 7-membered,partially unsaturated, i.e. non-aromatic, heterocyclic groups and4-membered to 7-membered, saturated, heterocyclic groups. 4-membered to7-membered, saturated, heterocyclic groups are also comprised by thegroup Het¹. The rings of the groups Het and Het¹ thus can be 4-membered,5-membered, 6-membered or 7-membered, for example 5-membered or6-membered. In one embodiment of the invention, a partially unsaturatedgroup Het comprises one or two, in another embodiment one, double bondswithin the ring which can be present in any position. In one embodimentof the invention, a 4-membered group Het is saturated. In one embodimentof the invention, a group Het is a 4-membered to 7-membered saturatedgroup or a 5-membered or 6-membered aromatic group, in anotherembodiment a group Het is a is a 4-membered to 7-membered saturatedgroup, and in another embodiment a group Het is a 5-membered or6-membered aromatic group. The groups Het and Het¹ can be bonded via anyring carbon atom or ring nitrogen atom. Examples of groups Het and Het¹are azetidinyl including azetidin-1-yl, oxetanyl including oxetan-3-yl,tetrahydrofuranyl including tetrahydrofuran-2-yl andtetrahydrofuran-3-yl, tetrahydrothiophenyl includingtetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl,1-oxo-tetrahydrothiophenyl including 1-oxo-tetrahydrothiophen-2-yl and1-oxo-tetrahydrothiophen-3-yl, 1,1-dioxo-tetrahydrothiophenyl including1,1-dioxo-tetrahydrothiophen-2-yl and 1,1-dioxo-tetrahydrothiophen-3-yl,pyrrolidinyl including pyrrolidin-1-yl, pyrrolidin-2-yl andpyrrolidin-3-yl, tetrahydropyranyl including tetrahydropyran-2-yl,tetrahydropyran-3-yl and tetrahydropyran-4-yl, tetrahydrothiopyranylincluding tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl andtetrahydrothiopyran-4-yl, piperidinyl including piperidin-1-yl,piperidin-2-yl, piperidin-3-yl and piperidin-4-yl,1,2,3,4-tetrahydropyridinyl including 1,2,3,4-tetrahydropyridin-1-yl,1,2,3,6-tetrahydropyridinyl including 1,2,3,6-tetrahydropyridin-1-yl,oxepanyl including oxepan-2-yl, oxepan-3-yl and oxepan-4-yl, azepanylincluding azepan-1-yl, azepan-2-yl, azepan-3-yl and azepan-4-yl,1,3-dioxolanyl including 1,3-dioxolan-2-yl and 1,3-dioxolan-4-yl,imidazolidinyl including imidazolidin-1-yl, imidazolidin-2-yl andimidazolidin-4-yl, [1,3]oxazolidinyl including [1,3]oxazolidin-2-yl,[1,3]oxazolidin-3-yl, [1,3]oxazolidin-4-yl and [1,3]oxazolidin-5-yl,[1,3]thiazolidinyl including [1,3]thiazolidin-2-yl,[1,3]thiazolidin-3-yl, [1,3]thiazolidin-4-yl and [1,3]thiazolidin-5-yl,[1,3]dioxanyl including [1,3]dioxan-2-yl, [1,3]dioxan-4-yl and[1,3]dioxan-5-yl, [1,4]dioxanyl including [1,4]dioxan-2-yl, piperazinylincluding piperazin-1-yl and piperazin-2-yl, morpholinyl includingmorpholin-2-yl, morpholin-3-yl and morpholin-4-yl, thiomorpholinylincluding thiomorpholin-2-yl, thiomorpholin-3-yl and thiomorpholin-4-yl,1-oxo-thiomorpholinyl including 1-oxo-thiomorpholin-2-yl,1-oxo-thiomorpholin-3-yl and 1-oxo-thiomorpholin-4-yl,1,1-dioxo-thiomorpholinyl including 1,1-dioxo-thiomorpholin-2-yl,1,1-dioxo-thiomorpholin-3-yl and 1,1-dioxo-thiomorpholin-4-yl,[1,3]diazepanyl, [1,4]diazepanyl, [1,4]oxazepanyl or [1,4]thiazepanyl.Besides by oxo groups in the ring members S(O) and S(O)₂ and alkylgroups representing R⁶⁰, the groups Het and Het¹ are optionallysubstituted on ring carbon atoms by one or more, for example 1, 2, 3, 4or 5, or 1, 2, 3 or 4, or 1, 2 or 3, identical or different substituentsas indicated, which can be located in any positions.

The 3-membered to 10-membered, monocyclic, bicyclic or tricyclic ringwhich is saturated or unsaturated and which contains 0, 1, 2 or 3identical or different hetero ring members chosen from the seriesconsisting of N,N(R³²), O, S, S(O) and S(O)₂, which ring can representR²⁴, can comprise 3, 4, 5, 6, 7, 8, 9 or 10 ring members. In oneembodiment of the invention, a bicyclic and tricyclic ring is fused orbridged. An unsaturated ring can be partially unsaturated and contain,for example, one or two double bonds within the ring, or, in the case ofa monocyclic or bicyclic ring, be aromatic in one or both rings, andaltogether the number of double bonds within an unsaturated ring can beone, two, three, four or five. In a bicyclic ring, the two individualrings can independently of each other be saturated or partiallyunsaturated or aromatic, and in a tricyclic ring the individual rings,independently of each other, can in particular be saturated or partiallyunsaturated. In one embodiment of the invention, a 3-membered or4-membered ring is saturated. The 3-membered to 10-membered, monocyclic,bicyclic or tricyclic ring can be a carbocyclic ring, i.e. contain 0(zero) hetero ring members, or a heterocyclic ring in which hetero ringmembers can be present as indicated above. In a bicyclic heterocyclicring one or both individual rings can contain hetero ring members, andin a tricyclic ring one or more individual rings can contain hetero ringmembers. In case nitrogen atoms are present as hetero ring members in abicyclic or tricyclic ring, they can also be present at a fusionposition or a bridgehead position. The free bond via which the ring isbonded to the group R²³, can be located at any suitable ring carbon atomor ring nitrogen atom. In one embodiment of the invention the free bondis located at a ring carbon atom. In general, besides by oxo groups inthe ring members S(O) and S(O)₂ and substituents R³² on ring nitrogenatoms, the 3-membered to 10 membered ring is optionally substituted onring carbon atoms by one or more, for example 1, 2, 3, 4 or 5, or 1, 2,3 or 4, or 1, 2 or 3, identical or different substituents as indicated,which can be located in any positions.

The 3-membered to 10-membered, monocyclic, bicyclic or tricyclic ringcomprises (C₃-C₇)-cycloalkyl groups, phenyl groups, and monocyclic,5-membered or 6-membered aromatic heterocyclic groups and monocyclic4-membered to 7-membered partially unsaturated and saturated groups asare comprised by the definitions of the groups Het, Het¹ and Het². Allthese groups thus are examples of the said 3-membered to 10-memberedring, and all explanations given above with respect to these groupsapply correspondingly to the said 3-membered to 10-membered ring unlessspecified otherwise in the definition of the said 3-membered to10-membered ring. Thus, for example, the substituents in these groups,such as in a phenyl group which represents the said 3-membered to10-membered ring, or in a monocyclic 5-membered or 6-membered aromaticheterocyclic group representing the group Het or Het² which representsthe said 3-membered to 10-membered ring, can then be as is specified inthe definition of R²⁴. As further examples of cyclic groups which arecomprised by the said 3-membered to 10-membered ring,(C₅-C₇)-cycloalkenyl groups, naphthalenyl groups and hydrogenatednaphthalenyl groups, indenyl groups and hydrogenated indenyl groups,bicyclic heterocyclic groups, and bicycloalkyl, bicycloalkenyl andtricycloalkyl groups and hetero analogs thereof may be mentioned.

In a (C₅-C₇)-cycloalkenyl group representing R²⁴, the number of ringcarbon atoms can be 5, 6 or 7. Examples of cycloalkenyl groups arecyclopentenyl including cyclopent-1-enyl, cyclopent-2-enyl andcyclopent-3-enyl, cyclohexyl including cyclohex-1-enyl, cyclohex-2-enyland cyclohex-3-enyl, and cycloheptyl including cyclohept-1-enyl,cyclohept-2-enyl, cyclohept-3-enyl and cyclohept-4-enyl. Cycloalkenylgroups representing R²⁴ can be unsubstituted or substituted as indicatedwith respect to the 3-membered to 10-membered ring representing R²⁴, forexample by one or more, or 1, 2, 3 or 4, or 1, 2 or 3, identical ordifferent (C₁-C₄)-alkyl substituents, for example by methyl groups,which can be located in any positions. Examples of suchalkyl-substituted cycloalkenyl groups are 1-methylcyclopent-2-enyl,1-methylcyclopent-3-enyl, 2,3-dimethylcyclohex-2-enyl and3,4-dimethylcyclohex-3-enyl. Cycloalkenyl groups also are optionallysubstituted by one or more fluorine substituents, i.e., they can beunsubstituted by fluorine and not carry any fluorine substituents, orsubstituted, for example by 1, 2, 3, 4, 5, 6 or 7, or by 1, 2, 3, 4 or5, or by 1, 2, 3 or 4, fluorine substituents. Cycloalkenyl groups canalso be substituted simultaneously by fluorine and alkyl. The fluorineatoms can be located in any positions of the cycloalkenyl group and canalso be located in an alkyl substituent on the cycloalkenyl group.Examples of fluoro-substituted cycloalkyl groups are1-fluorocyclohex-2-enyl, 1-fluorocyclohex-3-enyl and4,4-difluorocyclohex-2-enyl.

Naphthalenyl groups (naphthyl groups) representing R²⁴ can benaphthalen-1-yl (1-naphthyl) and naphthalen-2-yl (2-naphthyl) groups,and are optionally substituted by one or more, for example by 1, 2, 3, 4or 5, or by 1, 2 or 3, for example by 1 or 2, identical or differentsubstituents as indicated above. The substituents in a substitutednaphthalenyl group can be located in any positions, for example in the2-position, 3-position, 4-position, 5-position, 6-position, 7-positionor 8-position in the case of a monosubstituted naphthalen-1-yl group andin the 1-position, 3-position, 4-position, 5-position, 6-position,7-position or 8-position in the case of a monosubstitutednaphthalen-2-yl group. Likewise, in a naphthalenyl group which carriestwo or more substituents, the substituents can be located in the ring towhich the remainder of the molecule is bonded, and/or in the other ring.Examples of hydrogenated naphthalenyl groups representing R²⁴ aredihydronaphthalenyl including 1,4-dihydronaphthalenyl,tetrahydronaphthalenyl including 1,2,3,4-tetrahydronaphthalenyl and5,6,7,8-tetrahydronaphthalenyl, octahydronaphthalenyl including1,2,3,4,5,6,7,8-octahydronaphthalenyl, and decahydronaphthalenyl.Hydrogenated naphthalenyl groups can be bonded to the remainder of themolecule via any ring carbon atom in a saturated or partiallyunsaturated or aromatic ring and are optionally substituted by one ormore, for example by 1, 2, 3, 4 or 5, or by 1, 2 or 3, for example by 1or 2, identical or different substituents as indicated above which canbe located in any positions.

Indenyl groups representing R²⁴ can be 1H-inden-1-yl, 1H-inden-2-yl,1H-inden-3-yl, 1H-inden-4-yl, 1H-inden-5-yl, 1H-inden-6-yl or1H-inden-7-yl, for example, and are optionally substituted by one ormore, for example by 1, 2, 3, 4 or 5, or by 1, 2 or 3, for example by 1or 2, identical or different substituents as indicated above which canbe located in any positions. Examples of hydrogenated indenyl groupsrepresenting R²⁴ are indanyl (2,3-dihydro-1H-indenyl) andoctahydro-1H-indenyl, which can be bonded to the remainder of themolecule via any ring carbon atom in a saturated or partiallyunsaturated or aromatic ring, for example via the 1-position,2-position, 4-position or 5-position in the case of an indanyl group,and are optionally substituted by one or more, for example by 1, 2, 3, 4or 5, or by 1, 2 or 3, for example by 1 or 2, identical or differentsubstituents as indicated above which can be located in any positions.

In one embodiment of the invention, bicyclic heterocyclic groupsrepresenting R²⁴ are fused bicyclic groups in which the two rings have abond in common, and can be saturated, partially unsaturated or aromaticas indicated above with respect to the 3-membered to 10-membered ringrepresenting R²⁴ in general. They can contain 1, 2, 3, 4 or 5 doublebonds within the rings. Both of the rings can be saturated, or one ofthe rings can be saturated or partially unsaturated and the other ringpartially unsaturated or aromatic, or both rings can be aromatic, i.e.comprise a cyclic system of six delocalized pi electrons. In oneembodiment of the invention, both rings are aromatic or one of the ringsis aromatic and the other ring is partially unsaturated and comprises atleast one double bond due to the condensation to the aromatic ring. Inone embodiment of the invention, a bicyclic heterocyclic group comprises8, 9 or 10 ring members and two fused 5-membered rings or two fused6-membered rings or a 6-membered ring fused to a 5-membered ring or a7-membered ring fused to a 5-membered ring, in another embodiment 9 or10 ring members and two fused 6-membered rings or a 6-membered ringfused to a 5-membered ring. Hetero ring members can be present in bothrings of a bicyclic heterocyclic group or in one of the rings only andthe other ring contain no hetero ring members. Ring nitrogen atoms canalso be common to both rings. Besides being a hetero ring member inother 3-membered to 10-membered rings representing R²⁴ such as saturatedrings, a ring nitrogen atom carrying a group R³² can be the ringnitrogen atom in a fused 5-membered ring in an aromatic bicyclicheterocyclic group, such as in a fused pyrrole, pyrazole, imidazole ortriazole, to which an exocyclic atom or group is bonded. Examples ofrings from which a fused bicyclic heterocyclic group can be derived, areindole, isoindole, benzo[b]thiophene, benzofuran, benzo[1,3]dioxole([1,3]benzodioxole, 1,2-methylenedioxybenzene), benzo[1,3]oxazole,benzo[1,3]thiazole, benzoimidazole, chromane, isochromane,benzo[1,4]dioxane ([1,4]benzodioxane, 1,2-ethylenedioxybenzene),quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline,phthalazine, pyrroloazepines, imidazoazepines, thienothiophenes,thienopyrroles, thienopyridines, naphthyridines, and the respectiverings in which one or some or all of the double bonds are hydrogenated,i.e. replaced with single bonds, such as 2,3-dihydro-1H-indole,2,3-dihydro-1H-isoindole, 2,3-dihydrobenzofuran,1,2,3,4-tetrahydroquinoline, 5,6,7,8-tetrahydroquinoline,decahydroquinoline, 1,2,3,4-tetrahydroisoquinoline,5,6,7,8-tetrahydroisoquinoline, decahydroisoquinoline, for example. Abicyclic heterocyclic group can be bonded via any ring carbon atom orring nitrogen atom. In one embodiment of the invention, a bicyclicheteroaromatic group is bonded via a ring carbon atom. For example, anindolyl group can be indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl,indol-5-yl, indol-6- or indol-7-yl, a benzoimidazolyl group can be1H-benzoimidazol-1-yl, 1H-benzoimidazol-2-yl, 1H-benzoimidazol-4-yl,1H-benzoimidazol-5-yl, 1H-benzoimidazol-6-yl or 1H-benzoimidazol-7-yl, abenzo[1,4]dioxanyl group can be benzo[1,4]dioxan-2-yl,benzo[1,4]dioxan-5-yl or benzo[1,4]dioxan-6-yl, a quinolinyl group(quinolyl group) can be quinolin-2-yl, quinolin-3-yl, quinolin-4-yl,quinolin-5-yl, quinolin-6-yl, quinolin-7-yl or quinolin-8-yl, anisoquinolinyl group can be isoquinolin-1-yl, isoquinolin-3-yl,isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-ylor isoquinolin-8-yl. In a substituted bicyclic heteroaromatic group, thesubstituents can be located in any desired positions such as, forexample, in an indol-2-yl group in the 1-position and/or the 3-positionand/or the 4-position and/or the 5-position and/or the 6-position and/orthe 7-position, in an indol-5-yl group in the 1-position and/or the2-position and/or the 3-position and/or the 4-position and/or the6-position and/or the 7-position, in a 1H-benzoimidazol-2-yl group inthe 1-position and/or the 4-position and/or the 5-position and/or the6-position and/or the 7-position. Generally, besides the substituentsindicated above, a bicyclic heterocyclic group can also carry onsuitable ring nitrogen atoms in aromatic rings, for example the nitrogenatom in a quinolinyl group or isoquinolinyl group, an oxido substituent—O⁻ and be present as an N-oxide.

In one embodiment of the invention, bicycloalkyl, bicycloalkenyl andtricycloalkyl groups representing R²⁴ are bridged 6-membered to10-membered, in another embodiment 7-membered to 10-membered, bicyclicand tricyclic groups which can contain carbon atoms only as ringmembers, i.e. they can be derived from carbocyclic bicycloalkanes,bicycloalkenes and tricycloalkanes, or which can also contain heteroring members as indicated above, i.e. they can be derived from therespective heteroanalogous aza-, oxa- and thia-bicycloalkanes,-bicycloalkenes and-tricycloalkanes. If they contain hetero ringmembers, in one embodiment they contain one or two hetero ring members,in another embodiment one hetero ring member, for example ring memberschosen from the series consisting of N,N(R²⁸) and O. The hetero ringmembers can be present in any desired positions in the bicyclic ortricyclic system including positions in the bridges and, in the case ofnitrogen atoms, positions at the bridgeheads. Bicycloalkenyl and theirhetero analogs can contain one or more double bonds within the rings. Inone embodiment of the invention they contain one or two double bonds, inanother embodiment one double bond, within the ring. Bicycloalkyl,bicycloalkenyl and tricycloalkyl can be bonded to the remainder of themolecule via any ring carbon atom or ring nitrogen atom. The free bondcan be located in any stereochemical position, for example in an exoposition or an endo position. Bicycloalkyl, bicycloalkenyl andtricycloalkyl and their hetero analogs are optionally substituted asindicated above, for example by substituents chosen from the seriesconsisting of (C₁-C₄)-alkyl, (C₂-C₅)-alkenyl, HO—, HO—CH₂—(hydroxymethyl-) and oxo, in any positions. Examples of bicycloalkyl,bicycloalkenyl and tricycloalkyl groups and hetero analogs thereof arenorbornyl (bicyclo[2.2.1]heptyl), bicyclo[3.1.1]heptyl,bicyclo[3.1.1]hept-2-enyl, bicyclo[2.2.2]octyl,bicyclo[2.2.2]oct-2-enyl, bicyclo[3.2.1]octyl, 7-azabicylo[2.2.1]heptyl,1-azabicyclo[2.2.2]octyl, bicyclo[2.2.2.]oct-2-en-yl,tricyclo[4.4.0.0^(3,8)]decyl), adamantyl (tricyclo[3.3.1.1^(3,7)]decyl),noradamantyl (tricyclo[3.3.1.0^(3,7)]nonyl),tricyclo[2.2.1.0^(2,6)]heptyl.

Halogen is fluorine, chlorine, bromine or iodine. In one embodiment ofthe invention, halogen is fluorine, chlorine or bromine, in anotherembodiment fluorine or chlorine.

An oxo group, i.e. a doubly bonded oxygen atom, when bonded to a carbonatom, replaces two hydrogen atoms on a carbon atom of the parent system.Thus, if a CH₂ group is substituted by oxo, it becomes a carbonyl group(C(O), C═O). An oxo group cannot occur as a substituent on a carbon atomin an aromatic ring such as in a phenyl group.

The present invention comprises all stereoisomeric forms of thecompounds of the formula I, for example all enantiomers anddiastereomers including cis/trans isomers. The invention likewisecomprises mixtures of two or more stereoisomeric forms, for examplemixtures of enantiomers and/or diastereomers including cis/transisomers, in all ratios. Asymmetric centers contained in the compounds ofthe formula I, for example in unsubstituted or substituted alkyl groups,can all independently of each other have the S configuration or the Rconfiguration. The invention relates to enantiomers, both thelevorotatory and the dextrorotatory antipode, in enantiomerically pureform and essentially enantiomerically pure form and in the form ofracemates and in the form of mixtures of the two enantiomers in allratios. The invention likewise relates to diastereomers in the form ofpure and essentially pure diastereomers and in the form of mixtures oftwo or more diastereomers in all ratios. The invention also comprisesall cis/trans isomers of the compounds of the formula I in pure form andessentially pure form and in the form of mixtures of the cis isomer andthe trans isomer in all ratios. Cis/trans isomerism can occur insubstituted rings and on double bonds, for example. The preparation ofindividual stereoisomers, if desired, can be carried out by resolutionof a mixture according to customary methods, for example, bychromatography or crystallization, or by use of stereochemically uniformstarting compounds in the synthesis or by stereoselective reactions.Optionally, before a separation of stereoisomers a derivatization can becarried out. The separation of a mixture of stereoisomers can be carriedout at the stage of the compound of the formula I or at the stage of anintermediate in the course of the synthesis. The invention alsocomprises all tautomeric forms of the compounds of the formula I.

Physiologically acceptable salts, including pharmaceutically utilizablesalts, of the compounds of the formula I generally comprise a nontoxicsalt component. They can contain inorganic or organic salt components.Such salts can be formed, for example, from compounds of the formula Iwhich contain an acidic group, for example a carboxylic acid group(hydroxycarbonyl group, HO—C(O)—), and nontoxic inorganic or organicbases. Suitable bases are, for example, alkali metal compounds oralkaline earth metal compounds, such as sodium hydroxide, potassiumhydroxide, sodium carbonate or sodium hydrogencarbonate, or ammonia,organic amino compounds and quaternary ammonium hydroxides. Reactions ofcompounds of the formula I with bases for the preparation of the saltsare in general carried out according to customary procedures in asolvent or diluent. Examples of salts of acidic groups thus are sodium,potassium, magnesium or calcium salts or ammonium salts which can alsocarry one or more organic groups on the nitrogen atom. Compounds of theformula I which contain a basic, i.e. protonatable, group, for examplean amino group or a basic heterocycle, can be present in the form oftheir acid addition salts with physiologically acceptable acids, forexample as salt with hydrogen chloride, hydrogen bromide, phosphoricacid, sulfuric acid, acetic acid, benzoic acid, methanesulfonic acid,p-toluenesulfonic acid, which in general can be prepared from thecompounds of the formula I by reaction with an acid in a solvent ordiluent according to customary procedures. If the compounds of theformula I simultaneously contain an acidic and a basic group in themolecule, the invention also includes internal salts (betaines,zwitterions) in addition to the salt forms mentioned. The presentinvention also comprises all salts of the compounds of the formula Iwhich, because of low physiological tolerability, are not directlysuitable for use as a pharmaceutical, but are suitable as intermediatesfor chemical reactions or for the preparation of physiologicallyacceptable salts, for example by means of anion exchange or cationexchange. The present invention also comprises all solvates of thecompounds of the formula I and their salts, including physiologicallyacceptable solvates, such as hydrates, i.e. adducts with water, andadducts with alcohols like (C₁-C₄)-alkanols, as well as activemetabolites of compounds of the formula I and prodrugs of the compoundsof the formula I, i.e. compounds which in vitro may not necessarilyexhibit pharmacological activity but which in vivo are converted intopharmacologically active compounds of the formula I, for examplecompounds which are converted by metabolic hydrolysis into a compound ofthe formula I, such as compounds in which a carboxylic acid group ispresent in esterified form or in the form of an amide.

As indicated above, the hetero ring members in the ring A, which ringincludes the two carbon atoms which also are part of the fused5-membered ring depicted in formula I carrying the groups R³ to R⁶, canbe present in any combination and can be located in any suitableposition. For example, in the case of a pyridine ring or a thiophenerepresenting A, the ring nitrogen atom or sulfur atom can be present ina position which is adjacent to the said 5-membered ring, or in aposition which is not adjacent to the said 5-membered ring. In case thering A is a 6-membered heterocyclic ring which comprises two hetero ringmembers N, for example, both hetero ring members can be present in thetwo positions adjacent to the said 5-membered ring and the 6-memberedring be a pyrazine ring, or one of them can be present in a positionadjacent to the said 5-membered ring and the other in a non-adjacentposition and the 6-membered ring be a pyrimidine ring or a pyridazinering, or both hetero ring members can be present in non-adjacentpositions and the 6-membered ring be a pyridazine ring. In oneembodiment of the invention, the hetero ring members in a heterocyclicring representing A are chosen from N and S, in another embodiment theyare N. In one embodiment of the invention, a cycloalkane ringrepresenting A is 5-membered, 6-membered or 7-membered, in anotherembodiment 5-membered or 6-membered, in another embodiment 6-membered,and the cycloalkane ring thus is a cyclopentane, cyclohexane orcycloheptane ring which can all be substituted as indicated. In oneembodiment of the invention the ring A is a cyclohexane ring, a benzenering, a pyridine ring, a pyrazine ring or a monocyclic 5-memberedaromatic heterocyclic ring comprising 1 or 2 identical or differenthetero ring members chosen from the series consisting of N,N(R¹), O andS, for example 1 hetero ring member chosen from the series consisting ofN(R¹), O and S, such as a thiophene ring, which rings can all beoptionally substituted as indicated. In another embodiment the ring A isa benzene ring, a pyridine ring, a pyrazine ring or a monocyclic5-membered aromatic heterocyclic ring comprising 1 or 2 identical ordifferent hetero ring members chosen from the series consisting ofN,N(R¹), O and S, for example 1 hetero ring member chosen from theseries consisting of N(R¹), O and S, such as a thiophene ring, whichrings can all be optionally substituted as indicated. In anotherembodiment the ring A is a benzene ring or a monocyclic 5-memberedaromatic heterocyclic ring comprising 1 or 2 identical or differenthetero ring members chosen from the series consisting of N,N(R¹), O andS, for example 1 hetero ring member chosen from the series consisting ofN(R¹), O and S, such as a thiophene ring, which rings can all beoptionally substituted as indicated. In another embodiment the ring A isa benzene ring, a pyrazine ring or a thiophene ring, in anotherembodiment a benzene ring or a thiophene ring, which rings can all beoptionally substituted as indicated. In another embodiment of theinvention, the ring A is a benzene ring which is optionally substitutedas indicated. In another embodiment of the invention, the ring A is acycloalkane ring which is optionally substituted as indicated.

The number of the substituents which can optionally be present on thering A, depends on the size and the kind of the ring A and the number ofhetero ring members. In one embodiment of the invention the number ofoptional substituents is 1, 2, 3 or 4, in another embodiment 1, 2 or 3,in another embodiment 1 or 2, in another embodiment 1. For example, inthe case of a benzene ring representing A, which ring can beunsubstituted or substituted, the number of optional substituents can be1, 2, 3 or 4, or 1, 2 or 3, or 1 or 2, for example 1. In the case of apyridine ring, the number of optional substituents can be 1, 2 or 3, or1 or 2, for example 1, in the case of pyrazine ring, it can be 1 or 2,for example 1, in the case of a thiophene ring it can be 1 or 2, forexample 1, in the case of a thiazole ring it can be 1. In one embodimentof the invention, a cycloalkane ring representing A is not substitutedby any substituents. In another embodiment of the invention the ring Ais not substituted by any substituents and the ring carbon atoms thuscarry hydrogen atoms. Substituents on the ring A can be present in anysuitable position. In one embodiment of the invention, in compounds ofthe formula I in which the ring A is an optionally substituted benzenering, the substituents which are optionally present in positions 5 and 6of the indane ring comprising the said benzene ring representing A, arechosen from the series consisting of halogen, R¹, HO—, R¹—O—,R¹—C(O)—O—, R¹—S(O)₂—O—, R¹—S(O)_(m)—, H₂N—, R¹—NH—, R¹—N(R¹)—,R¹—C(O)—NH—, R¹—C(O)—N(R⁷¹)—, R¹—S(O)₂—NH—, R¹—S(O)₂, —N(R⁷¹)—,R¹—C(O)—, HO—C(O)—, R¹—O—C(O)—, H₂N—C(O)—, R¹—NH—C(O)—, R¹—N(R¹)—C(O)—,H₂N—S(O)₂—, R¹—NH—S(O)₂—, R¹—N(R¹)—S(O)₂—, NC— and O₂N—. In anotherembodiment of the invention, in compounds of the formula I in which thering A is an optionally substituted benzene ring, the substituents whichare optionally present in the ring A are chosen from the seriesconsisting of halogen, R¹, HO—, R¹—O—, R¹—C(O)—O—, R¹—S(O)₂—O—,R¹—S(O)_(m)—, H₂N—, R¹—NH—, R¹—N(R¹)—, R¹—C(O)—NH—, R¹—C(O)—N(R⁷¹)—,R¹—S(O)₂—NH—, R¹—S(O)₂—N(R⁷¹)—, R¹—C(O)—, HO—C(O)—, R¹—O—C(O)—,H₂N—C(O)—, R¹—NH—C(O)—, R¹—N(R¹)—C(O)—, H₂N—S(O)₂—, R¹—NH—S(O)₂—,R¹—N(R¹)—S(O)₂—, NC— and O₂N—. In another embodiment of the invention,the substituents in a benzene ring or a heterocyclic ring representing Aare chosen from the series consisting of halogen, R¹, HO—, R¹—O—,R¹—O(O)—O—, R¹—S(O)₂—O—, R¹, —S(O)_(m)—, H₂N—, R¹—NH—, R¹—N(R¹)—,R¹—C(O)—NH—, R¹—C(O)—N(R⁷¹)—, R¹—S(O)₂—NH—, R¹—S(O)₂—N(R⁷¹)—, R¹—C(O)—,HO—C(O)—, R¹—O—C(O)—, H₂N—C(O)—, R¹—NH—C(O)—, R¹—N(R¹)—C(O)—,H₂N—S(O)₂—, R¹—NH—S(O)₂—, R¹—N(R¹)—S(O)₂—, NC— and O₂N—, in anotherembodiment from the series consisting of halogen, R¹, HO—, R¹—O—,R¹—O(O)—O—, R¹—S(O)_(m)—, H₂N—, R¹—NH—, R¹—N(R¹)—, R¹—C(O)—NH—,R¹—C(O)—N(R⁷¹)—, R¹—S(O)₂—NH—, R¹—S(O)₂—N(R⁷¹)—, NC— and O₂N—, inanother embodiment from the series consisting of halogen, R¹, R¹—O—,R¹—S(O)_(m)—, NC— and O₂N—, for example from the series consisting ofhalogen, (C₁—O₄)-alkyl, (C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_(m)—, NC—and O₂N—, in another embodiment from the series consisting of halogen,R¹, R¹—O—, R¹—S(O)_(m)— and NC—, for example from the series consistingof halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—, (C₁—O₄)-alkyl-S(O)_(m)— andNC—, in another embodiment from the series consisting of halogen, R¹,R¹—O— and NC—, for example from the series consisting of halogen,(C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and NC—, in another embodiment from theseries consisting of halogen, R¹ and R¹—O—, for example from the seriesconsisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—. In oneembodiment of the invention the substituents in a benzene ring or aheterocyclic ring representing A are chosen from the series consistingof halogen and (C₁-C₄)-alkyl. In one embodiment of the invention, thenumber of nitro substituents (C₂N—) on the ring A is not greater thantwo, in another embodiment not greater than one. In one embodiment ofthe invention, the total number of nitro groups in a compound of theformula I is not greater than two.

In case the ring A is a benzene ring, the compounds of the formula I canalso be represented by the formula Ia,

wherein Y, Z, R³ to R⁶, R²⁰ to R²² and R⁵⁰ are defined as in thecompounds of the formula I, R⁷ is defined as the substituents which areoptionally present in a benzene ring representing the ring A in thecompounds of the formula I, i.e. R⁷ is chosen from the series consistingof halogen, R¹, HO—, R¹—O—, R¹—C(O)—O—, R¹—S(O)₂—O—, R¹—S(O)_(m)—, H₂N—,R¹—NH—, R¹—N(R¹)—, R¹—C(O)—NH—, R¹—C(O)—N(R⁷¹)—, R¹—S(O)₂—NH—,R¹—S(O)₂—N(R⁷¹)—, R¹—C(O)—, HO—C(O)—, R¹—O—C(O)—, H₂N—C(O)—,R¹—NH—C(O)—, R¹—N(R¹)—C(O)—, H₂N—S(O)₂—, R¹—NH—S(O)₂—, R¹—N(R¹)—S(O)₂—,NC—, O₂N—, phenyl and Het, or from any of the other series ofsubstituents indicated herein, for example from the series consisting ofhalogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_(m)— andNC—, or from the series consisting of halogen and (C₁-C₄)-alkyl, and thenumber r is 0, 1, 2, 3 or 4, or is 0, 1, 2 or 3, or is 0, 1 or 2, or is0 or 1. In one embodiment of the invention, the number r in thecompounds of the formula Ia is 0, i.e. the benzene ring depicted informula Ia does not carry a substituent R⁷. The substituents R⁷ can bepresent on any of the four carbon atoms of the benzene ring depicted informula Ia which are not part of the fused 5-membered ring carrying thegroups R³ to R⁶. All other such carbon atoms of the benzene ring whichdo not carry a substituent R⁷, carry hydrogen atoms. I.e., in case thenumber r is 0, for example, the benzene ring carries four hydrogenatoms.

In a similar manner, in case the ring A is a pyridine ring, a pyridazinering, a thiophene ring, or a cyclohexane ring, for example, thecompounds of the formula I can be represented by the formulae Ib-1,Ib-2, Ic, Id-1, Id-2 and Ie,

wherein Y, Z, R³ to R⁶, R²⁰ to R²² and R⁶⁰ are defined as in thecompounds of the formula I, R⁷ is defined as the substituents which areoptionally present in the ring A in the compounds of the formula I, i.e.in the case of the compounds of the formulae Ib-1, Ib-2, Ic, Id-1 andId-2 R⁷ is chosen from the series consisting of halogen, R¹, HO—, R¹—O—,R¹—C(O)—O—, R¹—S(O)₂—O—, R¹—S(O)_(m)—, H₂N—, R¹—NH—, R¹—N(R¹)—,R¹—C(O)—NH—, R¹—C(O)—N(R⁷¹)—, R¹—S(O)₂—NH—, R¹—S(O)₂—N(R⁷¹)—, R¹—C(O)—,HO—C(O)—, R¹—O—C(O)—, H₂N—C(O)—, R¹—NH—C(O)—, R¹—N(R¹)—C(O)—,H₂N—S(O)₂—, R¹—NH—S(O)₂—, R¹—N(R¹)—S(O)₂—, NC—, O₂N—, phenyl and Het, orfrom any of the other series of substituents indicated herein, forexample from the series consisting of halogen, (C₁-C₄)-alkyl,(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_(m)— and NC—, or from the seriesconsisting of halogen and (C₁-C₄)-alkyl, and in the case of thecompounds of the formula Ie R⁷ is chosen from the series consisting offluorine and (C₁-C₄)-alkyl, and the number r is 0, 1, 2 or 3, or is 0, 1or 2, or is 0 or 1, in the case of the compounds of the formulae Ib-1and Ib-2, and is or 0, 1 or 2, or is 0 or 1, in the case of thecompounds of the formulae Ic, Id-1 and Id-2, and is 0, 1, 2, 3, 4, 5, 6,7 or 8, or is 0, 1, 2, 3 or 4, or is 0, 1 or 2, for example, in the caseof the compounds of the formula Ie. In one embodiment of the invention,the number r in the compounds of the formulae Ib-1, Ib-2, Ic, Id-1, Id-2and Ie is 0, i.e. the pyridine ring, pyridazine ring, thiophene ring andcyclohexane ring depicted in the formulae do not carry a substituent R⁷.The substituents R⁷ can be present on any ring carbon atoms, inparticular ring carbon atoms which are not part of the fused 5-memberedring carrying the groups R³ to R⁶. In positions on ring carbon atoms inwhich no substituent R⁷ is present, hydrogen atoms are present.

In the group C(R¹²)═C(R¹³) representing the divalent group Y, the carbonatom carrying the group R¹³ is bonded to the ring carbon atom carryingthe group R²¹ and the carbon atom carrying the group R¹² is bonded tothe ring carbon atom carrying the group C(O)—N(R²⁰). In the groupN═C(R¹⁴), the carbon atom carrying the group R¹⁴ is bonded to the ringcarbon atom carrying the group R²¹ and the nitrogen atom is bonded tothe ring carbon atom carrying the group C(O)—N(R²⁰). In the groupC(R¹⁵)═N, the nitrogen atom is bonded to the ring carbon atom carryingthe group R²¹ and the carbon atom carrying the group R¹⁵ is bonded tothe ring carbon atom carrying the group C(O)—N(R²⁰). In one embodimentof the invention, Y is chosen from the series consisting S,C(R¹²)═C(R¹³), N═C(R¹⁴) and C(R¹⁵)═N, in another embodiment from theseries consisting S, C(R¹²)═C(R¹³) and C(R¹⁵)═N. In one embodiment ofthe invention Y is chosen from the series consisting of S andC(R¹²)═C(R¹³), in another embodiment from the series consisting ofC(R¹²)═C(R¹³) and C(R¹⁵)═N. In another embodiment of the invention, Y isC(R¹²)═C(R¹³). In another embodiment of the invention, Y is C(R¹⁵)═N.

In one embodiment of the invention, the trivalent group Z is C(R¹⁶). Inanother embodiment Z is C(R¹⁶) and Y is chosen from the seriesconsisting of S, C(R¹²)═C(R¹³) and C(R¹⁵)═N. In another embodiment Z isC(R¹⁶) and Y is chosen from the series consisting of S andC(R¹²)═C(R¹³). In another embodiment Z is C(R¹⁶) and Y is chosen fromthe series consisting of C(R¹⁵)═N and C(R¹²)═C(R¹³). In this latterembodiment, the aromatic ring in the compounds of the formula Icomprising the ring members Y and Z is a pyridine ring or a benzenering, respectively, and the compounds of the formula I are compounds ofthe formula If or of the formula Ig,

wherein A, R³ to R⁶, R¹², R¹³, R¹⁵, R¹⁶, R²⁰ to R²² and R⁵⁰ are definedas in the compounds of the formula I or have any of their otherindicated meanings. In one embodiment of the invention the group Z isC(R¹⁶) and the group Y is S. In another embodiment of the invention thegroup Z is C(R¹⁶) and the group Y is C(R¹⁵)═N. In another embodiment ofthe invention the group Z is C(R¹⁶) and the group Y is C(R¹²)═C(R¹³),i.e., in this embodiment the compounds of the formula I are compounds ofthe formula Ig. In another embodiment of the invention, in the compoundsof the formula Ia the group Z is C(R¹⁶) and the group Y isC(R¹²)═C(R¹³), i.e., compounds of this embodiment are compounds of theformula Ih,

wherein R³ to R⁶, R¹², R¹³, R¹⁶, R²⁰ to R²² and R⁵⁰ are defined as inthe compounds of the formula I or have any of their other indicatedmeanings. R⁷ and r in the compounds of the formula Ih are defined as inthe compounds of the formula Ia and, like in the compounds of theformula Ia, the substituents R⁷ can be present on any of the four carbonatoms of the fused benzene ring depicted in formula Ih which are notpart of the fused 5-membered ring carrying the groups R³ to R⁶, and allother such carbon atoms of the benzene ring which do not carry asubstituent R⁷ carry hydrogen atoms. All explanations on groups and alldefinitions and embodiments specified above or below with respect to thecompounds of the formula I apply correspondingly to the compounds of allformulae which represent subgroups of the compounds of the formula I,including the compounds of the formulae Ia to Ih.

In one embodiment of the invention, R⁰ is chosen from the seriesconsisting of hydrogen and (C₁-C₄)-alkyl, in another embodiment from theseries consisting of hydrogen and methyl. In one embodiment of theinvention, R⁰ is hydrogen. In another embodiment of the invention R⁰ is(C₁-C₄)-alkyl, for example methyl.

In one embodiment of the invention, R¹, R², R¹¹, R³⁰, R³³, R³⁵, R⁵⁴,R⁵⁵, R⁵⁷ and R⁵⁸ are, independently of each other group R¹, R², R¹¹,R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, chosen from the series consistingof (C₁-C₆)-alkyl, (C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl, (C₃-C₇)-cycloalkyland (C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, in another embodiment from theseries consisting of (C₁-C₄)-alkyl, (C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl,(C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, in anotherembodiment from the series consisting of (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, in anotherembodiment from the series consisting of (C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, in anotherembodiment from the series consisting of (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-CH₂-alkyl-, in anotherembodiment from the series consisting of (C_(r) C₆)-alkyl and(C₃-C₇)-cycloalkyl, in another embodiment from the series consisting of(C₁-C₄)-alkyl and (C₃-C₇)-cycloalkyl, which are all optionallysubstituted by one or more identical or different substituents R⁷⁰,wherein in these groups besides any substituents R⁷⁰ one or morefluorine substituents are optionally present and in cycloalkyl groupsone or more (C₁-C₄)-alkyl substituents are optionally present as appliesto alkyl, alkenyl, alkynyl and cycloalkyl groups in general. In oneembodiment of the invention R¹, R², R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷and R⁵⁸ are, independently of each other group R¹, R², R¹¹, R³⁰, R³³,R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸ are, independently of series consisting of(C₁-C₆)-alkyl, in another embodiment from the series consisting of(C₁-C₄)-alkyl, which are all optionally substituted by one or moreidentical or different substituents R⁷⁰. In one embodiment of theinvention, (C₃-C₇)-cycloalkyl groups occurring in R¹, R², R¹¹, R³⁰, R³³,R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸ are, independently of each other group R¹,R², R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, (C₃-C₆)-cycloalkyl, inanother embodiment (C₃-C₄)-cycloalkyl, for example cyclopropyl, inanother embodiment (C₅-C₆)-cycloalkyl, for example cyclohexyl. In oneembodiment of the invention, the number of substituents R⁷⁰ in any ofthe groups R¹, R², R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸ is,independently of each other group R¹, R², R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵,R⁵⁷ and R⁵⁸, 0, 1, 2, 3 or 4, in another embodiment 0, 1, 2 or 3, inanother embodiment 0, 1 or 2, in another embodiment 0 or 1. In oneembodiment of the invention, any of the groups R¹, R², R¹¹, R³⁰, R³³,R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, independently of each other group R¹, R²,R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, does not carry a substituentR⁷⁰, but merely is optionally substituted by one or more fluorinesubstituents and, in the case of cycloalkyl groups, one or more(C₁-C₄)-alkyl substituents. In another embodiment of the invention, anyof the groups R¹, R², R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸,independently of each other group R¹, R², R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵,R⁵⁷ and R⁵⁸, does neither carry a substituent R⁷⁰ nor fluorinesubstituents nor, in the case of cycloalkyl groups, (C₁-C₄)-alkylsubstituents.

In one embodiment of the invention, a phenyl-(C₁-C₄)-alkyl- grouprepresenting R³ or R⁵ is a benzyl group wherein the phenyl moiety isoptionally substituted as indicated with respect to phenyl groups ingeneral. In one embodiment of the invention, one of the groups R³ and R⁵is chosen from the series consisting of hydrogen, (C₁-C₄)-alkyl,phenyl-(C₁-C₄)-alkyl-, phenyl and hydroxy and the other of the groups R³and R⁵ is chosen from the series consisting of hydrogen, (C₁-C₄)-alkyl,phenyl-(C₁-C₄)-alkyl- and phenyl. In one embodiment of the invention,the groups R³ and R⁵ are independently of each other chosen from theseries consisting of hydrogen, (C₁-C₄)-alkyl, phenyl-(C₁-C₄)-alkyl- andphenyl. In another embodiment, R³ and R⁵ are independently of each otherchosen from the series consisting of hydrogen and (C₁-C₄)-alkyl, inanother embodiment from the series consisting of hydrogen and methyl. Inanother embodiment, R³ and R⁵ are hydrogen.

In one embodiment of the invention, R⁴ and R⁶ are independently of eachother chosen from the series consisting of hydrogen and methyl. Inanother embodiment, R⁴ and R⁶ are hydrogen.

In one embodiment of the invention, R³ and R⁴ are identical and arechosen from the series consisting of hydrogen and methyl, in anotherembodiment they both are hydrogen. In another embodiment, R⁵ and R⁶ areidentical and are chosen from the series consisting of hydrogen andmethyl, and in another embodiment they both are hydrogen. In anotherembodiment R³, R⁴, R⁵ and R⁶ are all identical and are chosen from theseries consisting of hydrogen and methyl. In another embodiment R³, R⁴,R⁵ and R⁶ all are hydrogen.

In one embodiment of the invention, R¹⁰ is chosen from the seriesconsisting of hydrogen and methyl. In another embodiment R¹⁰ ishydrogen. In another embodiment of the invention R¹⁰ is (C₁-C₄)-alkyl,for example methyl.

In one embodiment of the invention, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ areindependently of each other chosen from the series consisting ofhydrogen, halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)_(m)—, H₂N—, (C₁-C₄)-alkyl-NH—,(C₁-C₄)-alkyl-N((C₁-C₄)-alkyl)-, NC— and O₂N—, in another embodimentfrom the series consisting of hydrogen, halogen, (C₁-C₄)-alkyl,(C₁-C₄)-alkyl-O—, NC— and O₂N—, in another embodiment from the seriesconsisting of hydrogen, halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— andO₂N—, in another embodiment from the series consisting of hydrogen,halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and NC—, in another embodimentfrom the series consisting of hydrogen, halogen, (C₁-C₄)-alkyl and(C₁-C₄)-alkyl-O—, in another embodiment from the series consisting ofhydrogen, halogen and (C₁-C₄)-alkyl. In one embodiment of the invention,R¹² and R¹³ are independently of each other chosen from the seriesconsisting of hydrogen, halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— andNC—, in another embodiment from the series consisting of hydrogen,halogen, (C₁-C₄)-alkyl and NC—, in another embodiment from the seriesconsisting of hydrogen, halogen and NC—, in another embodiment from theseries consisting of hydrogen and halogen, in another embodiment fromthe series consisting of hydrogen, chlorine and fluorine, in anotherembodiment from the series consisting of hydrogen and fluorine. In oneembodiment of the invention, R¹² is hydrogen and R¹³ is fluorine or R¹²is fluorine and R¹³ is hydrogen. In another embodiment R¹² and R¹³ arehydrogen. In one embodiment of the invention, R¹⁴ and R¹⁵ areindependently of each other chosen from the series consisting ofhydrogen, halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in anotherembodiment from the series consisting of hydrogen, halogen and(C₁-C₄)-alkyl, in another embodiment from the series consisting ofhydrogen and halogen, in another embodiment from the series consistingof hydrogen, chlorine and fluorine. In another embodiment of theinvention, R¹⁴ and R¹⁵ are hydrogen. In one embodiment of the invention,R¹⁶ is chosen from the series consisting of hydrogen, halogen,(C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in another embodiment from theseries consisting of hydrogen, halogen and (C₁-C₄)-alkyl, in anotherembodiment from the series consisting of hydrogen and halogen, inanother embodiment from the series consisting of hydrogen, chlorine andfluorine. In another embodiment of the invention, R¹⁶ is hydrogen.

In one embodiment of the invention, R²⁰ is chosen from the seriesconsisting of hydrogen and methyl. In another embodiment R²⁰ ishydrogen. In another embodiment R²⁰ is (C₁-C₄)-alkyl, for examplemethyl.

In one embodiment of the invention the group R²¹ is a group of theformula II, i.e. of the formula R²⁴—R²³—, which is bonded to theremainder of the molecule through the moiety R²³ as is symbolized withrespect to this group and in general by a terminal hyphen representingthe free bond, and the group R²² is chosen from the series consisting ofhydrogen, halogen, R³⁰, HO—, R³⁰—O—, R³⁰—C(O)—O—, R³⁰—S(O)₂—O—,R³⁰—S(O)_(m)—, H₂N—, R³⁰—NH—, R³⁰—N(R³⁰)—, R³⁰—C(O)—NH—,R³⁰—C(O)—N(R⁷¹)—, R³⁰—S(O)₂—NH—, R³⁰—S(O)₂—N(R⁷¹)—, R³⁰—C(O)—, HO—C(O)—,R³⁰—O—C(O)—, H₂N—C(O)—, R³⁰—NH—C(O)—, R³⁰—N(R³⁰)—C(O)—, H₂N—S(O)₂—,R³⁰—NH—S(O)₂—, R³⁰—N(R³⁰)—S(O)₂—, NC—, O₂N— and Het¹. In anotherembodiment, the group R²² is a group of the formula II and the group R²¹is chosen from the series consisting of hydrogen, halogen, R³⁰, HO—,R³⁰—O—, R³⁰—C(O)—O—, R³⁰—S(O)₂—O—, R³⁰—S(O)_(m)—, H₂N—, R³⁰—NH—,R³⁰—N(R³⁰)—, R³⁰—C(O)—NH—, R³⁰—C(O)—N(R⁷¹)—, R³⁰—S(O)₂—NH—,R³⁰—S(O)₂—N(R⁷¹)—, R³⁰—C(O)—, HO—C(O)—, R³⁰—O—C(O)—, H₂N—C(O)—,R³⁰—NH—C(O)—, R³⁰—N(R³⁰)—C(O)—, H₂N—S(O)₂—, R³⁰—NH—S(O)₂—,R³⁰—N(R³⁰)—S(O)₂—, NC—, O₂N— and Het¹.

In one embodiment of the invention, the one of the groups R²¹ and R²²which is not a group of the formula II, is chosen from the seriesconsisting of hydrogen, halogen, R³⁰, R³⁰—O—, R³⁰—C(O)—O—,R³⁰—S(O)_(m)—, H₂N—, R³⁰—NH—, R³⁰—N(R³⁰)—, R³⁰—C(O)—NH—, R³⁰—C(O)— andNC—, in another embodiment from the series consisting of hydrogen,halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)_(m)—, H₂N—, (C₁-C₄)-alkyl-NH—, di((C₁-C₄)-alkyl)N—,(C₁-C₄)-alkyl-C(O)— and NC—, in another embodiment from the seriesconsisting of hydrogen, halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_(m)—, (C₁-C₄)-alkyl-C(O)— and NC—,in another embodiment from the series consisting of halogen,(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)_(m)—, H₂N—, (C₁-C₄)-alkyl-NH—, di((C₁-C₄)-alkyl)N—,(C₁-C₄)-alkyl-C(O)— and NC—, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)_(m)—, H₂N—, (C₁-C₄)-alkyl-NH—, di((C₁-C₄)-alkyl)N—,(C₁-C₄)-alkyl-C(O)— and NC—, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)_(m)—, (C₁-C₄)-alkyl-NH—, di((C₁-C₄)-alkyl)N— and(C₁-C₄)-alkyl-C(O)—. In one embodiment of the invention, the one of thegroups R²¹ and R²² which is not a group of the formula II, is chosenfrom the series consisting of (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)_(m)—, (C₁-C₄)-alkyl-NH— and di((C₁-C₄)-alkyl)N—, inanother embodiment from the series consisting of (C₁-C₄)-alkyl,(C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-S(O)_(m)—, in another embodiment fromthe series consisting of (C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-S(O)_(m)—.In another embodiment, the one of the groups R²¹ and R²² which is not agroup of the formula II, is chosen from the series consisting of(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O— and(C₁-C₄)-alkyl-C(O)—, in another embodiment from the series consisting of(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl- and (C₁-C₄)-alkyl-O—, in anotherembodiment from the series consisting of (C₁-C₄)-alkyl and(C₁-C₄)-alkyl-O—. In another embodiment, the one of the groups R²¹ andR²² which is not a group of the formula II, is (C₁-C₄)-alkyl-O—, forexample methoxy or ethoxy.

In one embodiment of the invention, in case the group R²¹ is a group ofthe formula II, the group R²² is chosen from the series consisting of(C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, and in another embodiment it is(C₁-C₄)-alkyl-O—, and in case the group R²² is a group of the formulaII, the group R²¹ is chosen from the series consisting of hydrogen,halogen, R³⁰, HO—, R³⁰—O—, R³⁰—C(O)—O—, R³⁰—S(O)₂—O—, R³⁰—S(O)_(m)—,H₂N—, R³⁰—NH—, R³⁰—N(R³⁰)—, R³⁰—C(O)—NH—, R³⁰—C(O)—N(R⁷¹)—,R³⁰—S(O)₂—NH—, R³⁰—S(O)₂—N(R⁷¹)—, R³⁰—C(O)—, HO—C(O)—, R³⁰—O—C(O)—,H₂N—C(O)—, R³⁰—NH—C(O)—, R³⁰—N(R³⁰)—C(O)—, H₂N—S(O)₂—, R³⁰—NH—S(O)₂—,R³⁰—N(R³⁰)—S(O)₂—, NC—, O₂N— and Het¹, or is defined as in any of theembodiments or other definitions of R²¹ specified herein.

The number of chain members in a chain representing R²³ can be 1, 2, 3,4 or 5. In one embodiment of the invention, the divalent group R²³ is adirect bond, i.e. the group R²⁴ is directly bonded to the ringcomprising the groups Y and Z which is depicted in formula I. In anotherembodiment R²³ is a direct bond or a chain consisting of 1, 2, 3 or 4chain members. In another embodiment R²³ is a direct bond or a chainconsisting of 2, 3 or 4 chain members, in another embodiment a directbond or a chain consisting of 2 or 3 chain members, in anotherembodiment a direct bond or a chain consisting of 3 chain members,wherein in these embodiments the chain members are defined as above orbelow. In another embodiment R²³ is a chain consisting of 1, 2, 3, 4 or5 chain members, in another embodiment a chain consisting of 1, 2, 3 or4 chain members, in another embodiment a chain consisting of 2, 3 or 4chain members, in another embodiment a chain consisting of 2 or 3 chainmembers, in another embodiment a chain consisting of 3 chain members,wherein in these embodiments the chain members are defined as above orbelow. In one embodiment of the invention, zero or one of the chainmembers in a chain representing R²³ is a hetero chain member, and inanother embodiment one of the chain members in a chain representing R²³is a hetero chain member, wherein in these embodiments the hetero chainmembers are defined as above or below. In another embodiment of theinvention, none of the chain members in a chain representing R²³ is ahetero chain member. In one embodiment of the invention, the heterochain members in a chain representing R²³ are chosen from the seriesconsisting of N(R²⁵), O, S and S(O)₂. In another embodiment of theinvention, the hetero chain members in a chain representing R²³ arechosen from the series consisting of N(R²⁵), O and S, in anotherembodiment from the series consisting of N(R²⁵) and O, in anotherembodiment from the series consisting of O and S, in another embodimentfrom the series consisting of N(R²⁵), O and S(O)₂, in another embodimentfrom the series consisting of N(R²⁵) and S(O)₂, in another embodimentfrom the series consisting of O and S(O)₂. In another embodiment of theinvention, the hetero chain members which can be present in a chainrepresenting R²³, are O (oxygen), and in another embodiment the heterochain members which can be present in a chain representing R²³, areN(R²⁵). In another embodiment of the invention, zero or one hetero chainmember is present in a chain representing R²³ which is O (oxygen), andin another embodiment one hetero chain member is present which is O. Inanother embodiment of the invention, zero or one hetero chain member ispresent in a chain representing R²³ which is N(R²⁵), and in anotherembodiment one hetero chain member is present which is N(R²⁵).

Hetero chain members in a chain representing R²³ can be present in anypositions of the chain provided that the resulting moiety complies withthe prerequisites specified above with respect to R²³ and the compoundsof the invention in general. In case two adjacent groups C(R²⁶)(R²⁶) ina chain representing R²³ are connected to each other by a double bond ortriple bond, in one embodiment of the invention hetero chain members arenot present in positions adjacent to such a double bond or triple bond.

Hetero chain members can be present at any one end or at both ends ofthe chain, and can thus be directly bonded to the group R²⁴ and/or thering comprising the groups Y and Z which is depicted in formula I,and/or inside the chain. In case one or two hetero chain members arepresent in a chain representing R²³, in one embodiment of the inventionat least one of the terminal chain members is a hetero chain member, andin another embodiment the terminal chain member which is bonded to thegroup R²⁴ is a hetero chain member, and in another embodiment theterminal chain member which is bonded to the ring comprising the groupsY and Z is a hetero chain member. In one embodiment of the invention,one of the chain members in a chain representing R²³ is a hetero chainmember and this hetero chain member is the terminal chain member bondedto the group R²⁴. In another embodiment, one of the chain members in achain representing R²³ is a hetero chain member and this hetero chainmember is the terminal chain member bonded to the ring comprising thegroups Y and Z which is depicted in formula I.

If two adjacent groups C(R²⁶)(R²⁶) within a chain representing R²³ areconnected to each other by a double bond or a triple bond, the chainthus comprises an unsaturated divalent group of the formula—C(R²⁶)^(=c)(R²⁶)—, wherein R²⁶ is defined as above and in oneembodiment of the invention is chosen from the series consisting ofhydrogen and (C₁-C₄)-alkyl, or an unsaturated group of the formula—C═C—. Chain members which are not connected to each other by a doublebond or triple bond, are connected to each other by a single bond. If adouble bond is present between two adjacent groups C(R²⁶)(R²⁶), one ofthe groups R²⁶ in each of the two adjacent groups C(R²⁶)(R²⁶) can beregarded as being a free bond, the two free bonds together then forminga second bond between the respective carbon atoms. If a triple bond ispresent between two adjacent groups C(R²⁶)(R²⁶), both groups R²⁶ in eachof the two adjacent groups C(R²⁶)(R²⁶) can be regarded as being a freebond, the two pairs of free bonds together then forming a second and athird bond between the respective carbon atoms. In one embodiment of theinvention, the said unsaturated group is present not more than once in achain representing R²³. The said unsaturated group can be present in anyposition of a chain representing R²³ and occur at any one end of thechain, and can thus be bonded directly to the group R²⁴ and/or the ringcomprising the groups Y and Z which is depicted in formula I, or occurinside the chain. In one embodiment of the invention the saidunsaturated group is not adjacent to a hetero chain member. In oneembodiment of the invention, a chain representing R²³ does not contain adouble bond or triple bond. In another embodiment it is possible for twoadjacent groups C(R²⁶)(R²⁶) to be connected to each other by a doublebond. In another embodiment it is possible for two adjacent groupsC(R²⁶)(R²⁶) to be connected to each other by a triple bond. In anotherembodiment two adjacent groups C(R²⁶)(R²⁶) are connected to each otherby a triple bond, i.e., in this embodiment a chain representing R²³comprises a triple bond. In a another embodiment the group R²³ is agroup of the formula —C≡C—.

In one embodiment of the invention R²³ is chosen from a direct bond andfrom any one or more of the chains which are present in the followingexamples of groups of the formula II, which groups are bonded to thering comprising the groups Y and Z which is depicted in formula I by thefree bond represented by the terminal hyphen, and from which groups ofthe formula II the groups R²³ themselves are obtained by removing thegroup R²⁴:

R²⁴—C(R²⁶)(R²⁶)—, R²⁴—C(R²⁶)(R²⁶)—C(R²⁶)(R²⁶)—, R²⁴—C≡C—,R²⁴—C(R²⁶)(R²⁶)—O—, R²⁴—C(R²⁶)(R²⁶)—S—, R²⁴—C(R²⁶)(R²⁶)—N(R²⁵)—,R²⁴—S(O)₂—O—, R²⁴—C(R²⁶)(R²⁶)—C(R²⁶)(R²⁶)—C(R²⁶)(R²⁶)—,R²⁴—C(R²⁶)═C(R²⁶)—C(R²⁶)(R²⁶)—, R²⁴—C(R²⁶)(R²⁶)—C(R²⁶)(R²⁶)—O—,R²⁴—O—C(R²⁶)(R²⁶)—C(R²⁶)(R²⁶)—, R²⁴—C(R²⁶)(R²⁶)—O—C(R²⁶)(R²⁶)—,R²⁴—C(R²⁶)(R²⁶)—C(R²⁶)(R²⁶)—S—, R²⁴—C(R²⁶)(R²⁶)—S—C(R²⁶)(R²⁶)—,R²⁴—S—C(R²⁶)(R²⁶)—C(R²⁶)(R²⁶)—, R²⁴—C(R²⁶)(R²⁶)—C(R²⁶)(R²⁶)—N(R²⁵)—,wherein in these groups of the formula II the groups R²⁴, R²⁵ and R²⁶are defined as above or below.

In one embodiment of the invention, R²⁴ is chosen from the seriesconsisting of R³¹, R³¹—O—, R³¹—S(O)_(m)—, H₂N—, R³¹—NH—, R³¹—N(R³¹)—,R³¹—C(O)—NH—, R³¹—C(O)—N(R⁷¹)—, HO—C(O)—, R³¹—O—C(O)—, H₂N—C(O)—,R³¹—NH—C(O)—, R³¹—N(R³¹)—C(O)—, NC— and a 3-membered to 10-membered,monocyclic, bicyclic or tricyclic ring, in another embodiment from theseries consisting of R³¹, R³¹—O—, R³¹—S(O)_(m)—, NC— and a 3-membered to10-membered, monocyclic, bicyclic or tricyclic ring, in anotherembodiment from the series consisting of R³¹, R³¹—O— and a 3-membered to10-membered, monocyclic, bicyclic or tricyclic ring, in anotherembodiment from the series consisting of (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-O—and a 3-membered to 10-membered, monocyclic, bicyclic or tricyclic ring,wherein in all these embodiments the 3-membered to 10-membered,monocyclic, bicyclic or tricyclic ring is defined as above or below andis saturated or unsaturated and contains 0, 1, 2 or 3 identical ordifferent hetero ring members chosen from the series consisting ofN,N(R³²), O, S, S(O) and S(O)₂ and is optionally substituted on ringcarbon atoms by one or more identical or different substituents chosenfrom the series consisting of halogen, R³³, HO—, R³³—O—, R³³—C(O)—O—,R³³—S(O)₂—O—, R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—,R³³—C(O)—N(R⁷¹)—, R³³—S(O)₂—NH—, R³³—S(O)₂—N(R⁷¹)—, H₂N—S(O)₂—NH—,R³³—NH—S(O)₂—NH—, R³³—N(R³³)—S(O)₂—NH—, H₂N—S(O)₂—N(R⁷¹)—,R³³—NH—S(O)₂—N(R⁷¹)—, R³³—N(R³³)—S(O)₂—N(R⁷¹)—, R³³—C(O)—, HO—C(O)—,R³³—O—C(O)—, H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)—, H₂N—S(O)₂—,R³³—NH—S(O)₂—, R³³—N(R³³)—S(O)₂—, NC—, O₂N—, oxo, phenyl and Het, or hasany of its other meanings indicated herein. In another embodiment of theinvention R²⁴ is a 3-membered to 10-membered, monocyclic, bicyclic ortricyclic ring which is defined as above or below and is saturated orunsaturated and contains 0, 1, 2 or 3 identical or different hetero ringmembers chosen from the series consisting of N,N(R³²), O, S, S(O) andS(O)₂, which ring is optionally substituted on ring carbon atoms by oneor more identical or different substituents chosen from the seriesconsisting of halogen, R³³, HO—, R³³—O—, R³³—C(O)—O—, R³³—S(O)₂—O—,R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—,R³³—C(O)—N(R⁷¹)—, R³³—S(O)₂—NH—, R³³—S(O)₂—N(R⁷¹)—, H₂N—S(O)₂—NH—,R³³—NH—S(O)₂—NH—, R³³—N(R³³)—S(O)₂—NH—, H₂N—S(O)₂—N(R⁷¹)—,R³³—NH—S(O)₂—N(R⁷¹)—, R³³—N(R³³)—S(O)₂—N(R⁷¹)—, R³³—C(O)—, HO—C(O)—,R³³—O—C(O)—, H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)—, H₂N—S(O)₂—,R³³—NH—S(O)₂—, R³³—N(R³³)—S(O)₂—, NC—, O₂N—, oxo, phenyl and Het, or hasany of its other meanings indicated herein.

In one embodiment of the invention, a 3-membered to 10-membered,monocyclic, bicyclic or tricyclic ring representing R²⁴ is a monocyclicor bicyclic ring, and in another embodiment it is a monocyclic ring,which rings are all optionally substituted as indicated above or below.In one embodiment of the invention, a monocyclic ring representing R²⁴is 3-membered to 7-membered, in another embodiment 3-membered or5-membered to 7-membered, in another embodiment 3-membered, 5-memberedor 6-membered, in another embodiment 5-membered or 6-membered, inanother embodiment 6-membered, which rings are all optionallysubstituted as indicated above or below. In one embodiment of theinvention, a bicyclic or tricyclic ring representing R²⁴ is 7-memberedto 10-membered, which rings are all optionally substituted as indicatedabove or below. In one embodiment of the invention, a ring representingR²⁴ is a saturated ring or an unsaturated ring including a partiallyunsaturated, i.e. non-aromatic, ring which contains zero, one, two orthree, for example zero, one or two, double bonds, within the ring, oran aromatic ring, which rings are all optionally substituted asindicated above or below. In another embodiment, a ring representing R²⁴is a saturated ring or a partially unsaturated ring which contains zero,one, two or three, for example zero, one or two, double bonds within thering, which rings are all optionally substituted as indicated above orbelow. In another embodiment of the invention, a ring representing R²⁴is an aromatic ring, in another embodiment an aromatic ring chosen frombenzene, aromatic 5-membered and 6-membered monocyclic heterocycles,naphthalene and aromatic 9-membered and 10-membered bicyclicheterocycles, in another embodiment an aromatic ring chosen from benzeneand aromatic 5-membered and 6-membered monocyclic heterocycles, inanother embodiment an aromatic ring chosen from benzene and thiophene,which rings are all optionally substituted as indicated above or below.In another embodiment, a ring representing R²⁴ is a benzene ring whichis optionally substituted as indicated above or below, i.e. by thesubstituents specified above or below with respect to the 3-membered to10-membered ring representing R²⁴. In terms of residues, in this latterembodiment R²⁴ is a phenyl group which is optionally substituted asindicated above or below, i.e. by the substituents specified above orbelow with respect to the 3-membered to 10-membered ring representingR²⁴.

In one embodiment of the invention, the number of hetero ring memberswhich can be present in a 3-membered to 10-membered ring representingR²⁴ is 0, 1 or 2, in another embodiment of the invention the number ofhetero ring members is 0 or 1, and in another embodiment of theinvention the number of hetero ring members is 0 (zero), i.e., in thislatter embodiment a 3-membered to 10-membered ring representing R²⁴ is acarbocyclic ring, which rings are all optionally substituted asindicated above or below. In one embodiment of the invention, the heteroring members which can be present in a 3-membered to 10-membered ringrepresenting R²⁴ are chosen from N,N(R³²), O, S and S(O)₂, in anotherembodiment from N, N(R³²), O and S, in another embodiment from N, O andS, in another embodiment from N(R³²), O and S, in another embodimentfrom N and S.

In one embodiment of the invention, the number of substituents which areoptionally present on ring carbon atoms in a 3-membered to 10-memberedring representing R²⁴ is 1, 2, 3, 4, or 5, in another embodiment thenumber of substituents which are optionally present on ring carbon atomsis 1, 2, 3 or 4, in another embodiment the number of substituents whichare optionally present on ring carbon atoms is 1, 2 or 3, in anotherembodiment the number of substituents which are optionally present onring carbon atoms is 1 or 2.

In one embodiment of the invention, the substituents which areoptionally present on ring carbon atoms in a 3-membered to 10-memberedring representing R²⁴, including a benzene ring or a phenyl group,respectively, representing R²⁴, are chosen from the series consisting ofhalogen, R³³, HO—, R³³—O—, R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—,R³³—C(O)—NH—, R³³—C(O)—N(R⁷¹)—, R³³—S(O)₂—NH—, R³³—S(O)₂—N(R⁷¹)—,H₂N—S(O)₂—NH—, R³³—NH—S(O)₂—NH—, R³³—N(R³³)—S(O)₂—NH—,H₂N—S(O)₂—N(R⁷¹)—, R³³—NH—S(O)₂—N(R⁷¹)—, R³³—N(R³³)—S(O)₂—N(R⁷¹)—,HO—C(O)—, R³³—O—C(O)—, H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)—, NC—,oxo, phenyl and Het, in another embodiment from the series consisting ofhalogen, R³³, HO—, R³³—O—, R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—,R³³—C(O)—NH—, R³³—C(O)—N(R⁷¹)—, R³³—S(O)₂—NH—, R³³—S(O)₂—N(R⁷¹)—,H₂N—S(O)₂—NH—, R³³—NH—S(O)₂—NH—, R³³—N(R³³)—S(O)₂—NH—,H₂N—S(O)₂—N(R⁷¹)—, R³³—NH—S(O)₂—N(R⁷¹)—, R³³—N(R³³)—S(O)₂—N(R⁷¹)—,HO—C(O)—, R³³—O—C(O)—, H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)— andNC—, in another embodiment from the series consisting of halogen, R³³,HO—, R³³—O—, R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—,R³³—S(O)₂—NH—, H₂N—S(O)₂—NH—, R³³—NH—S(O)₂—NH—, R³³—N(R³³)—S(O)₂—NH—,HO—C(O)—, R³³—O—C(O)—, H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)— andNC—, in another embodiment from the series consisting of halogen, R³³,HO—, R³³—O—, R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—,R³³—S(O)₂—NH—, H₂N—S(O)₂—NH—, R³³—NH—S(O)₂—NH—, R³³—N(R³³)—S(O)₂—NH—,H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—, in another embodimentfrom the series consisting of halogen, R³³, HO—, R³³—O—, R³³—S(O)_(m)—,H₂N—, R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—, R³³—S(O)₂—NH—, H₂N—C(O)—,R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—, in another embodiment from theseries consisting of halogen, R³³, HO—, R³³—O—, R³³—S(O)_(m)—, H₂N—,R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—, R³³—C(O)—N(R⁷¹)—, R³³—S(O)₂—NH—,R³³—S(O)₂—N(R⁷¹)—, H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—, inanother embodiment from the series consisting of halogen, R³³, HO—,R³³—O—, R³³—S(O)_(m)—, R³³—C(O)—NH—, R³³—C(O)—N(R⁷¹)—, R³³—S(O)₂—NH—,R³³—S(O)₂—N(R⁷¹)—, H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—, inanother embodiment from the series consisting of halogen, R³³, HO—,R³³—O—, R³³—S(O)_(m)—, R³³—C(O)—NH—, R³³—S(O)₂—NH—, H₂N—C(O)—,R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—, in another embodiment from theseries consisting of halogen, R³³, HO—, R³³—O—, R³³—C(O)—NH—,R³³—S(O)₂—NH—, H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—, inanother embodiment from the series consisting of halogen, R³³, R³³—O—,R³³—C(O)—NH—, R³³—S(O)₂—NH—, H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)—and NC—, in another embodiment from the series consisting of halogen,R³³, R³³—O— and NC—, in another embodiment from the series consisting ofhalogen, R³³ and R³³—O—, in another embodiment from the seriesconsisting of halogen and R³³, wherein in all these embodiments R³³ andR⁷¹ are defined as indicated above or below and R³³ is optionallysubstituted by one or more identical or different substituents R⁷⁰. Inone embodiment of the invention, the groups R³³ in these substituents ona ring representing R²⁴ are independently of each other chosen from theseries consisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, in another embodiment from the seriesconsisting of (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl and(C₃-C₆)-cycloalkyl-(C₁-C₂)-alkyl-, in another embodiment from the seriesconsisting of (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl and(C₃-C₆)-cycloalkyl-CH₂—, in another embodiment from the seriesconsisting of (C₁-C₆)-alkyl, cyclopropyl and cyclopropyl-CH₂—, forexample from the series consisting of (C₁-C₆)-alkyl, in anotherembodiment from the series consisting of (C₁-C₄)-alkyl, cyclopropyl andcyclopropyl-CH₂—, for example from the series consisting of(C₁-C₄)-alkyl. In one embodiment of the invention, the number ofsubstituents R⁷⁰, which are optionally present in these groups R³³besides any fluorine substituents and, in the case of cycloalkyl groups,any (C₁-C₄)-alkyl substituents, is independently of each other 0, 1, 2or 3, in another embodiment 0, 1 or 2, in another embodiment 0 or 1, inanother embodiment 0. In one embodiment of the invention, thesubstituents R⁷⁰ in these groups R³³ are independently of each otherchosen from the series consisting of HO—, R⁷¹—O—, R⁷¹—C(O)—O—, H₂N—,R⁷¹—NH—, R⁷¹—N(R⁷¹)—, R⁷¹—C(O)—NH—, R⁷¹—C(O)—N(R⁷¹)—, R⁷¹—S(O)₂—NH— andR⁷¹—S(O)₂—N(R⁷¹)—, in another embodiment from the series consisting ofHO—, R⁷¹—C(O)—O—, H₂N—, R⁷¹—C(O)—NH— and R⁷¹—S(O)₂—NH—, in anotherembodiment from the series consisting of HO—, R⁷¹—C(O)—O— andR⁷¹—C(O)—NH—, in another embodiment from the series consisting of HO—and R⁷¹—C(O)—NH—, in another embodiment from the series consisting ofHO— and R⁷¹—O—, and in another embodiment of the invention substituentsR⁷⁰ in these groups R³³ are HO—. In one embodiment of the invention, thegroups R⁷¹ present in these groups R³³ are independently of each otherchosen from the series consisting of (C₁-C₄)-alkyl, cyclopropyl andcyclopropyl-, in another embodiment from the series consisting of(C₁-C₄)-alkyl and cyclopropyl, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl. In one embodiment of the invention, R²⁴ isa benzene ring or a thiophene ring, for example a benzene ring, or, interms of the respective residues, R²⁴ is a phenyl group or a thiophenyl(thienyl) group, for example a phenyl group, which are all optionallysubstituted as indicated afore.

Examples of specific residues of benzene and thiophene rings, i.e. ofspecific phenyl and thiophenyl groups, representing R²⁴, from any one ormore of which examples the group R²⁴ is chosen in one embodiment of theinvention, are phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl,2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 3-bromo-phenyl,2,3-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-difluoro-phenyl,2,5-dichloro-phenyl, 2-chloro-6-fluoro-phenyl, 3,4,5-trifluoro-phenyl,3-methyl-phenyl (m-tolyl), 3-ethyl-phenyl, 3-isopropyl-phenyl,3-cyclopropyl-phenyl, 3-tert-butyl-5-methyl-phenyl,3-trifluoromethyl-phenyl, 3-(2-hydroxyethyl)-phenyl,3-(2-hydroxy-2-methyl-propyl)-phenyl, 3-(2-acetylaminoethyl)-phenyl,2-fluoro-5-methyl-phenyl, 3-chloro-2-methyl-phenyl,5-chloro-2-methyl-phenyl, 5-chloro-2-fluoro-3-methyl-phenyl,2-fluoro-3-trifluoromethyl-phenyl, 2-fluoro-5-trifluoromethyl-phenyl,4-fluoro-3-trifluoromethyl-phenyl, 5-fluoro-3-trifluoromethyl-phenyl,3-chloro-4-trifluoromethyl-phenyl, 5-chloro-2-trifluoromethyl-phenyl,5-chloro-3-trifluoromethyl-phenyl, 3-ethoxy-phenyl, 2-propoxy-phenyl,3-isopropoxy-phenyl, 3-trifluoromethoxy-phenyl,3-(2,2,2-trifluoroethoxy)-phenyl, 5-chloro-2-methoxy-phenyl,3-chloro-4-methoxy-phenyl, 5-fluoro-3-isopropoxy-phenyl,2-fluoro-3-trifluoromethoxy-phenyl, 4-methoxy-3,5-dimethyl-phenyl,3-methoxy-5-trifluoromethyl-phenyl, 3-methylsulfanyl-phenyl,3-ethylsulfanyl-phenyl, 3-trifluoromethylsulfanyl-phenyl,3-ethanesulfonyl-phenyl, 3-acetylamino-phenyl,3-methanesulfonylamino-phenyl, 3-dimethylaminosulfonylamino-phenyl,3-cyano-phenyl, 2-thienyl, 3-thienyl, 4-methyl-2-thienyl,5-methyl-3-thienyl.

In one embodiment of the invention, the total number of C, N, O and Satoms which is present in the two groups R²³ and R²⁴, i.e. in thesubstituent group R²⁴—R²³— on the ring comprising the groups Y and Zwhich is depicted in formula I, is at least 6, in another embodiment atleast 7, in another embodiment at least 8, in another embodiment atleast 9.

In one embodiment of the invention, R²⁵ is chosen from the seriesconsisting of hydrogen and methyl, in another embodiment R²⁵ ishydrogen. In another embodiment of the invention R²⁵ is (C₁-C₄)-alkyl,for example methyl.

In one embodiment of the invention, R²⁶, independently of each othergroup R²⁶, is chosen from the series consisting of hydrogen, fluorine,methyl and HO—, in another embodiment from the series consisting ofhydrogen, fluorine and (C₁-C₄)-alkyl, in another embodiment from theseries consisting of hydrogen, fluorine and methyl, in anotherembodiment from the series consisting of hydrogen and fluorine, inanother embodiment from the series consisting of hydrogen and methyl,and in another embodiment R²⁶ is hydrogen, or in all these embodimentstwo groups R²⁶ bonded to the same carbon atom together are oxo, or twoof the groups R²⁶ or one group R²⁵ and one group R²⁶, together with thecomprised chain members, form a 3-membered to 7-membered monocyclic ringwhich is saturated and contains 0, 1 or 2 identical or different heteroring members chosen from the series consisting of N,N(R³⁴), O, S, S(O)and S(O)₂, which ring is optionally substituted on ring carbon atoms byone more identical or different substituents chosen from the seriesconsisting of fluorine and (C₁-C₄)-alkyl. In another embodiment of theinvention, R²⁶, independently of each other group R²⁶, is chosen fromthe series consisting of hydrogen, fluorine, methyl and HO—, in anotherembodiment from the series consisting of hydrogen, fluorine and(C₁-C₄)-alkyl, in another embodiment from the series consisting ofhydrogen, fluorine and methyl, in another embodiment from the seriesconsisting of hydrogen and fluorine, in another embodiment from theseries consisting of hydrogen and methyl, and in another embodiment R²⁶is hydrogen, or in all these embodiments two of the groups R²⁶ or onegroup R²⁵ and one group R²⁶, together with the comprised chain members,form a 3-membered to 7-membered monocyclic ring which is saturated andcontains 0, 1 or 2 identical or different hetero ring members chosenfrom the series consisting of N,N(R³⁴), O, S, S(O) and S(O)₂, which ringis optionally substituted on ring carbon atoms by one more identical ordifferent substituents chosen from the series consisting of fluorine and(C₁-C₄)-alkyl. In another embodiment of the invention, R²⁶,independently of each other group R²⁶, is chosen from the seriesconsisting of hydrogen, fluorine, methyl and HO—, in another embodimentfrom the series consisting of hydrogen, fluorine and (C₁-C₄)-alkyl, inanother embodiment from the series consisting of hydrogen, fluorine andmethyl, in another embodiment from the series consisting of hydrogen andfluorine, in another embodiment from the series consisting of hydrogenand methyl, and in another embodiment all groups R²⁶ are hydrogen.

In one embodiment of the invention, the number of groups R²⁶ in a chainrepresenting R²³ which are HO—, is zero, one or two, in anotherembodiment zero or one, in another embodiment zero, in anotherembodiment one. In one embodiment of the invention, a HO— grouprepresenting R²⁶ is not present on a carbon atom which is adjacent to ahetero chain member in a chain representing R²³. In another embodiment aHO— group representing R²⁶ is not bonded to a carbon atom which isconnected to an adjacent group C(R²⁶)(R²⁶) by a double bond. In oneembodiment of the invention the number of groups R²⁶ in a chainrepresenting R²³ which are (C₁-C₄)-alkyl such as methyl, is zero, one ortwo, in another embodiment zero or one, in another embodiment zero, inanother embodiment one, in another embodiment two. In one embodiment ofthe invention the number of groups R²⁶ in a chain representing R²³ whichare fluorine, is zero, one, two, three or four, in another embodimentzero, one, two or three, in another embodiment zero, one or two, inanother embodiment zero or one, in another embodiment zero, in anotherembodiment one, in another embodiment two. In one embodiment of theinvention, the number of oxo substituents in a chain representing R²³which are formed by two groups R²⁶ bonded to the same carbon atom, iszero, one or two, in another embodiment zero or one, in anotherembodiment zero, in another embodiment one. In one embodiment of theinvention, an oxo substituent in a chain representing R²³ is not presenton a carbon atom which is adjacent to a hetero chain member chosen fromthe series consisting of S(O) and S(O)₂, in another embodiment from theseries consisting of S, S(O) and S(O)₂, in another embodiment from theseries consisting of O, S, S(O) and S(O)₂.

In one embodiment of the invention, the number of rings which are formedby two of the groups R²⁶ or one group R²⁵ and one group R²⁶, togetherwith the comprised chain members, is zero, one or two, in anotherembodiment zero or one, in another embodiment one, in another embodimentzero. In one embodiment of the invention a ring formed by two of thegroups R²⁶ or one group R²⁵ and one group R²⁶, together with thecomprised chain members, is a 3-membered, 4-membered, 5-membered or6-membered ring, in another embodiment a 3-membered, 5-membered or6-membered ring, in another embodiment a 3-membered ring, in anotherembodiment a 5-membered or 6-membered ring. In one embodiment of theinvention, it is possible for two of the groups R²⁶, together with thecomprised chain members, to form a ring, but not for one group R²⁵ andone group R²⁶. In one embodiment of the invention the number of chainmembers which is comprised by a ring formed by two of the groups R²⁶ orone group R²⁵ and one group R²⁶, is one, two, three or four, in anotherembodiment it is one, two or three, in another embodiment it is one ortwo, in another embodiment it is one. In case such ring comprises onlyone chain member, the two of the groups R²⁶ forming the ring are bondedto the same carbon atom in the chain and the said one chain member isthe carbon atom carrying the two groups R²⁶. Examples of rings, whichare formed by two groups R²⁶ bonded to the same carbon atom and the onecomprised chain member, are cycloalkane rings such as cyclopropane,cyclobutane, cyclopentane or cyclohexane, and heterocyclic rings such astetrahydrothiophene, tetrahydrothiopyran, oxetane, tetrahydrofuran,tetrahydropyran, azetidine, pyrrolidine or piperidine, for examplecyclopropane, which carry any adjacent chain members of a chainrepresenting R²³ and/or the group R²⁴ and/or the ring comprising thegroups Y and Z which is depicted in formula I, on the same ring carbonatom, and which rings can all be substituted as indicated. In case aring formed by two of the groups R²⁶ or one group R²⁵ and one group R²⁶,together with the comprised chain members, comprises two chain members,the two groups R²⁶ forming the ring are bonded to two adjacent carbonatoms in the chain or the one group R²⁶ is bonded to a carbon atom whichis adjacent to the group N(R²⁵), respectively. Examples of rings, whichare formed in such case, are likewise cycloalkane rings such ascyclopropane, cyclobutane, cyclopentane or cyclohexane, and heterocyclicrings such as tetrahydrothiophene, tetrahydrothiopyran, oxetane,tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine or piperidine,for example cyclopropane, which carry any adjacent chain members of achain representing R²³ and/or the group R²⁴ and/or the ring comprisingthe groups Y and Z which is depicted in formula I, on two adjacent ringcarbon atoms or on the ring nitrogen atom and an adjacent ring carbonatom, and which rings can all be substituted as indicated.

In case a ring formed by two of the groups R²⁶ or one group R²⁵ and onegroup R²⁶, together with the comprised chain members, comprises morethan one chain members, besides at least one group C(R²⁶)(R²⁶) thecomprised chain members can also be hetero chain members including thegroup N(R²⁵) which then are hetero ring members of the formed ring. Inone embodiment of the invention, the total number of hetero ring membersin such a ring is zero, one or two, in another embodiment zero or one,in another embodiment zero, in another embodiment one. In one embodimentof the invention, hetero ring members in such a ring are chosen from theseries consisting of N,N(R³⁴), O and S, in another embodiment form theseries consisting of N,N(R³⁴) and O, in another embodiment from theseries consisting of N and N(R³⁴), in another embodiment from the seriesconsisting of N(R³⁴) and O, in another embodiment from the seriesconsisting of N(R³⁴), and in another embodiment hetero ring members insuch a ring are N, and in still another embodiment hetero ring membersin such a ring are O, wherein a hetero ring member N in a ring formed bytwo of the groups R²⁶ or one group R²⁵ and one group R²⁶, together withthe comprised chain members, is the nitrogen atom of a hetero chainmember N(R²⁵).

In one embodiment of the invention, the number of substituents which areoptionally present in a ring formed by two of the groups R²⁶ or onegroup R²⁵ and one group R²⁶, together with the comprised chain members,is 0, 1, 2, 3 or 4, in another embodiment 0, 1, 2 or 3, in anotherembodiment 0, 1 or 2, in another embodiment 0 or 1, in anotherembodiment 0. In one embodiment of the invention, (C₁-C₄)-alkylsubstituents which are present in a ring formed by two of the groups R²⁶or one group R²⁵ and one group R²⁶, together with the comprised chainmembers, are methyl. In one embodiment of the invention substituentspresent in a ring formed by two of the groups R²⁶ or one group R²⁵ andone group R²⁶, together with the comprised chain members, are fluorine,in another embodiment they are identical or different (C₁-C₄)-alkylgroups, for example methyl.

Examples of specific groups R²³ including specific groups R²⁶ containedtherein are given in the following examples of groups of the formula II,which groups are bonded to the ring comprising the groups Y and Z whichis depicted in formula I by the free bond represented by the terminalhyphen or the terminal line in the structural formula, and from whichgroups of the formula II the groups R²³ themselves are obtained byremoving the group R²⁴, wherein in these groups of the formula II thegroup R²⁴ is defined as above or below:

In one embodiment of the invention, R²³ is chosen from a direct bond andany one or more of the chains R²³ in the preceding examples of groups ofthe formula II and, likewise, the group of the formula II is chosen fromthe group R²⁴ and any one or more of the preceding examples of thegroups of the formula II.

In one embodiment of the invention, the number of substituents R⁷⁰ whichare optionally present in the group R³¹, is zero, one, two or three, inanother embodiment zero, one or two, in another embodiment zero or one,in another embodiment zero. In one embodiment of the invention, R³¹ ischosen from the series consisting of (C₁-C₆)-alkyl, in anotherembodiment from the series consisting of (C₁-C₄)-alkyl, which are alloptionally substituted by one or more identical or differentsubstituents R⁷⁰.

In one embodiment of the invention, R³² and R³⁴ are independently ofeach other chosen from the series consisting of hydrogen, R³⁵,R³⁵—C(O)—, R³⁵—O—C(O)—, phenyl and Het, in another embodiment from theseries consisting of hydrogen, R³⁵, R³⁵—C(O)—, R³⁵—O—C(O)—, phenyl andHet², in another embodiment from the series consisting of hydrogen, R³⁵,R³⁵—C(O)—, R³⁵—O—C(O)— and phenyl, in another embodiment from the seriesconsisting of hydrogen, R³⁵, R³⁵—C(O)— and R³⁵—O—C(O)—, in anotherembodiment from the series consisting of hydrogen, R³⁵ and R³⁵—C(O)—, inanother embodiment from the series consisting of hydrogen, R³⁵, phenyland Het, in another embodiment from the series consisting of hydrogen,R³⁵, phenyl and Het², in another embodiment from the series consistingof hydrogen, R³⁵ and phenyl, in another embodiment from the seriesconsisting of hydrogen and R³⁵, wherein in these embodiments a group Hetor Het² occurring in R³² and R³⁴ in one embodiment of the invention ischosen from pyridinyl and thiophenyl. In one embodiment of theinvention, the groups R³⁵ occurring in R³² and R³⁴ are independently ofeach other chosen from (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, in another embodiment from(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-,in another embodiment from (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-CH₂—, in another embodiment from (C₁-C₆)-alkyl and(C₃-C₇)-cycloalkyl, in another embodiment from (C₁-C₆)-alkyl, in anotherembodiment from (C₁-C₄)-alkyl, which are all optionally substituted byone or more identical or different substituents R⁷⁰ and wherein in thesegroups besides any substituents R⁷⁰ one or more fluorine substituentsare optionally present and in cycloalkyl groups one or more(C₁-C₄)-alkyl substituents are optionally present as applies to alkyland cycloalkyl groups in general.

In one embodiment of the invention, the number of substituents R⁷⁰ whichare optionally present in a group R³⁵ occurring in R³² and R³⁴ besidesany fluorine substituents and, in the case of a cycloalkyl group, alkylsubstituents, is, independently of each other group, 0, 1, 2, 3 or 4, inanother embodiment 0, 1, 2 or 3, in another embodiment 0, 1 or 2, inanother embodiment 0 or 1, in another embodiment 0. In one embodiment ofthe invention, substituents R⁷⁰ which are optionally present in a groupR³⁵ occurring in R³² and R³⁴ are, independently of each other group,chosen from the series consisting of HO—, R⁷¹—O—, NC—, phenyl and Het²,in another embodiment from the series consisting of phenyl and Het², inanother from the series consisting of phenyl, wherein phenyl and Het²are defined and optionally substituted as indicated.

In one embodiment of the invention, R⁵⁰ is chosen from R⁵¹—O— andR⁵²—NH—, in another embodiment from R⁵¹—O— and H₂N—. In anotherembodiment R⁵⁰ is R⁵¹—O—.

In one embodiment of the invention, R⁵¹ is hydrogen. In anotherembodiment of the invention, R⁵¹ is R⁵⁴.

In one embodiment of the invention, R⁵² is chosen from the seriesconsisting of hydrogen, R⁵⁵ and R⁵⁶—S(O)₂—, in another embodiment fromthe series consisting of hydrogen, (C₁-C₄)-alkyl which is optionallysubstituted by one or more identical or different substituents R⁷⁰, andR⁵⁶—S(O)₂—, in another embodiment from the series consisting ofhydrogen, unsubstituted (C₁-C₄)-alkyl and R⁵⁶—S(O)₂—, in anotherembodiment from the series consisting of hydrogen, unsubstituted methyland R⁵⁶—S(O)₂—, in another embodiment from the series consisting ofhydrogen and (C₁-C₄)-alkyl which is optionally substituted by one ormore identical or different substituents R⁷⁰, in another embodiment fromthe series consisting of hydrogen and unsubstituted (C₁-C₄)-alkyl, inanother embodiment from the series consisting of hydrogen andunsubstituted methyl. In another embodiment of the invention, R⁵² ishydrogen.

In one embodiment of the invention, R⁵³ is chosen from the seriesconsisting of hydrogen and (C₁-C₄)-alkyl which is optionally substitutedby one or more identical or different substituents R⁷⁰, in anotherembodiment from the series consisting of hydrogen and unsubstituted(C₁-C₄)-alkyl, in another embodiment from the series consisting ofhydrogen and unsubstituted methyl. In another embodiment of theinvention, R⁵³ is hydrogen.

In one embodiment of the invention, R⁵⁴ is chosen from (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, in anotherembodiment from (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, in another embodiment from(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-CH₂—, inanother embodiment from (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl, in anotherembodiment from (C₁-C₆)-alkyl, in another embodiment from (C₁-C₄)-alkyl,in another embodiment from (C₁-C₃)-alkyl, which are all optionallysubstituted by one or more identical or different substituents R⁷⁰ andwherein in these groups besides any substituents R⁷⁰ one or morefluorine substituents are optionally present and in cycloalkyl groupsone or more (C₁-C₄)-alkyl substituents are optionally present as appliesto alkyl and cycloalkyl groups in general. In one embodiment of theinvention, the number of substituents R⁷⁰ which are optionally presentin a group R⁵⁴ besides any fluorine substituents and, in the case of acycloalkyl group, any alkyl substituents, is 0, 1 or 2, in anotherembodiment 0 or 1, in another embodiment 1, in another embodiment 0. Inanother embodiment of the invention, a group R⁵⁴ is neither substitutedby R⁷⁰ nor by fluorine substituents nor, in the case of a cycloalkylgroup, by alkyl substituents, and R⁵⁴ in this embodiment thus is chosen,for example, from the series consisting of C₁—O₆)-alkyl,(C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, or from the series consisting of(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-CH₂—, or fromthe series consisting of (C₁-C₆)-alkyl, or from the series consisting of(C₁-C₄)-alkyl, or from the series consisting of (C₁-C₃)-alkyl, which areall unsubstituted. In one embodiment of the invention, substituents R⁷⁰which are optionally present in a group R⁵⁴, are independently of eachother chosen from the series consisting of HO—, R⁷¹—O—, R⁷¹—C(O)—O—,HO—C(O)— and R⁷¹—O—C(O)—, in another embodiment from the seriesconsisting of HO—, R⁷¹—O— and R⁷¹—C(O)—O—, in another embodiment fromthe series consisting of HO— and R⁷¹—C(O)—O—.

In one embodiment of the invention, R⁵⁶ is chosen from the seriesconsisting of phenyl which is optionally substituted as indicated aboveor below, and unsubstituted (C₁-C₄)-alkyl, in another embodiment fromthe series consisting of phenyl which is optionally substituted asindicated above or below, and unsubstituted methyl, in anotherembodiment from unsubstituted (C₁-C₄)-alkyl, in another embodiment fromunsubstituted(C₁-C₃)-alkyl. In another embodiment R⁵⁶ is unsubstitutedmethyl, in another embodiment phenyl which is optionally substituted asindicated.

In one embodiment of the invention, R⁶⁰ is chosen from the seriesconsisting of hydrogen and methyl. In another embodiment R⁶⁰ ishydrogen. In another embodiment R⁶⁰ is (C₁-C₄)-alkyl, for examplemethyl.

In one embodiment of the invention, a group R⁷⁰ in any of itsoccurrences is, independently of groups R⁷⁰ in other occurrences andunless specified otherwise, chosen from the series consisting of HO—,R⁷¹—O—, R⁷¹—C(O)—O—, R⁷¹—S(O)_(m)—, H₂N—, R⁷¹—NH—, R⁷¹—N(R⁷¹)—,R⁷¹—C(O)—NH—, R⁷¹—C(O)—N(R⁷¹)—, R⁷¹—S(O)₂—NH—, R⁷¹—S(O)₂—N(R⁷¹)—,HO—C(O)—, R⁷¹—O—C(O)—, H₂N—C(O)—, R⁷¹—NH—C(O)—, R⁷¹—N(R¹⁷)—C(O)—, NC—,oxo, phenyl and Het², in another embodiment from the series consistingof HO—, R⁷¹—O—, R⁷¹—C(O)—O—, R⁷¹—S(O)_(m)—, H₂N—, R⁷¹—NH—, R⁷¹—N(R⁷¹)—,R⁷¹—C(O)—NH—, R⁷¹—S(O)₂—NH—, HO—C(O)—, R⁷¹—O—C(O)—, H₂N—C(O)—,R⁷¹—NH—C(O)—, R⁷¹—N(R¹⁷)—C(O)—, NC—, oxo, phenyl and Het², in anotherembodiment from the series consisting of HO—, R⁷¹—O—, R⁷¹—C(O)—O—,R⁷¹—S(O)_(m)—, HO—C(O)—, R⁷¹—O—C(O)—, H₂N—C(O)—, R⁷¹—NH—C(O)—,R⁷¹—N(R¹⁷)—C(O)—, NC—, oxo, phenyl and Het², in another embodiment fromthe series consisting of HO—, R⁷¹—O—, R⁷¹—C(O)—O—, R⁷¹—S(O)_(m)—, H₂N—,R⁷¹—NH—, R⁷¹—N(R⁷¹)—, R⁷¹—C(O)—NH—, R⁷¹—S(O)₂—NH—, NC—, oxo, phenyl andHet², in another embodiment from the series consisting of HO—, R⁷¹—O—,R⁷¹—C(O)—O—, R⁷¹—S(O)_(m)—, NC—, oxo, phenyl and Het², in anotherembodiment from the series consisting of HO—, R⁷¹—O—, R⁷¹—S(O)_(m)—,NC—, oxo, phenyl and Het², in another embodiment from the seriesconsisting of HO—, R⁷¹—O—, R⁷¹—C(O)—O—, R⁷¹—S(O)_(m)—, NC—, phenyl andHet², in another embodiment from the series consisting of HO—, R⁷¹—O—,NC—, phenyl and Het², in another embodiment from the series consistingof HO—, R⁷¹—O—, phenyl and Het², in another embodiment from the seriesconsisting of HO—, R⁷¹—O— and phenyl, in another embodiment from theseries consisting of HO— and R⁷¹—O—, in another embodiment from theseries consisting of HO— and R⁷¹—C(O)—O—, in another embodiment from theseries consisting of phenyl and Het², in another embodiment from theseries consisting of phenyl, in another embodiment from the seriesconsisting of HO—C(O)—, R⁷¹—O—C(O)—, H₂N—C(O)—, R⁷¹—NH—C(O)—,R⁷¹—N(R¹⁷)—C(O)—, in another embodiment from the series consisting ofHO—C(O)—, and R⁷¹—O—C(O)—, and in another embodiment R⁷⁰ is HO—, whereinR⁷¹, phenyl and Het² are defined and optionally substituted as indicatedabove or below. In the latter embodiment, in which R⁷⁰ is HO—, a(C₁-C₆)-alkyl group, for example, which is optionally substituted by thesaid R⁷⁰, can among others be a group such as (C₁-C₆)-alkyl,HO—(C₁-C₆)-alkyl-, i.e. hydroxy-(C₁-C₆)-alkyl-, (HO)₂(C₂-C₆)-alkyl-,i.e. dihydroxy-(C₂-C₆)-alkyl-, and a (C₁-C₄)-alkyl group which isoptionally substituted by R⁷⁰, can among others be a group such as(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, i.e. hydroxy-(C₁-C₄)-alkyl-,(HO)₂(C₂-C₄)-alkyl-, i.e. dihydroxy-(C₂-C₄)-alkyl-, wherein the alkylgroups are optionally substituted by one or more fluorine substituents.In one embodiment of the invention, a carbon atom does not carry morethan one HO— group.

In one embodiment of the invention, R⁷¹ is chosen from (C₁-C₄)-alkyl,cyclopropyl and cyclopropyl-CH₂—, in another embodiment from(C₁-C₄)-alkyl and cyclopropyl, in another embodiment from (C₁-C₄)-alkyl,in another embodiment from (C₁-C₃)-alkyl, unless specified otherwise.

A subject of the invention are all compounds of the formula I whereinany one or more structural elements such as groups, substituents andnumbers are defined as in any of the specified embodiments ordefinitions of the elements or have one or more of the specific meaningswhich are mentioned herein as examples of elements, wherein allcombinations of one or more specified embodiments and/or definitionsand/or specific meanings of the elements are a subject of the presentinvention. Also with respect to all such compounds of the formula I, alltheir stereoisomeric forms and mixtures of stereoisomeric forms in anyratios, and their physiologically acceptable salts, and thephysiologically acceptable solvates of any of them, are a subject of thepresent invention.

Likewise, also with respect to all specific compounds disclosed herein,such as the example compounds which represent embodiments of theinvention wherein the various groups and numbers in the generaldefinition of the compounds of the formula I have the specific meaningspresent in the respective specific compound, it applies that all theirstereoisomeric forms and mixtures of stereoisomeric forms in any ratio,and their physiologically acceptable salts, and the physiologicallyacceptable solvates of any of them are a subject of the presentinvention. A subject of the invention also are all specific compoundsdisclosed herein, irrespective thereof whether they are disclosed as afree compound and/or as a specific salt, both in the form of the freecompound and in the form of all its physiologically acceptable salts,and if a specific salt is disclosed, additionally in the form of thisspecific salt, and the physiologically acceptable solvates of any ofthem. For example, in the case of the specific compound2-{2-chloro-5-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid which is disclosed in the form of the free compound, a subject ofthe invention are2-{2-chloro-5-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid and its physiologically acceptable salts and the physiologicallyacceptable solvates of any of them.

Thus, a subject of the invention also is a compound of the formula Iwhich is chosen from any of the specific compounds of the formula Iwhich are disclosed herein, or is any one of the specific compounds ofthe formula I which are disclosed herein, irrespective thereof whetherthey are disclosed as a free compound and/or as a specific salt, forexample a compound of the formula I which is chosen from

-   2-[4-methylsulfanyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic    acid,-   2-[4-acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic    acid,-   2-[4-ethyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic    acid,-   2-[4-ethoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic    acid,-   2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic    acid,-   2-{4-methoxy-3-[2-(3-trifluoromethylsulfanyl-phenyl)-ethoxy]-benzoylamino}-indane-2-carboxylic    acid,-   2-[4-methoxy-3-(1-m-tolyl-cyclopropylmethoxy)-benzoylamino]-indane-2-carboxylic    acid,-   2-{3-[2-(3-cyano-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylic    acid,-   5-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic    acid,-   5-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylic    acid,-   2-{[5-acetyl-4-(2-m-tolyl-ethoxy)-thiophene-2-carbonyl]-amino}-indane-2-carboxylic    acid,-   2-[3-fluoro-4-methoxy-5-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic    acid,-   2-[4-methoxy-3-(2-m-tolyloxy-ethyl)-benzoylamino]-indane-2-carboxylic    acid,-   2-[4-methoxy-3-(3-m-tolyl-propyl)-benzoylamino]-indane-2-carboxylic    acid,-   5-fluoro-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic    acid,-   2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dimethyl-indane-2-carboxylic    acid,-   2-[4-cyano-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic    acid,-   2-[4-methoxy-3-(2-m-tolyl-ethylamino)-benzoylamino]-indane-2-carboxylic    acid,-   2-{3-[2-(3-chloro-phenyl)-ethoxy]-4-methyl-benzoylamino}-indane-2-carboxylic    acid,-   2-[4-methoxy-3-(2-m-tolyl-ethylsulfanyl)-benzoylamino]-indane-2-carboxylic    acid,-   2-[3-(2-m-tolyl-ethoxy)-4-trifluoromethyl-benzoylamino]-indane-2-carboxylic    acid,-   2-{3-[2-(2-fluoro-5-methyl-phenyl)-ethoxy]-4-trifluoromethyl-benzoylamino}-indane-2-carboxylic    acid,-   2-(3-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylic    acid,-   2-{[6-methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-indane-2-carboxylic    acid,-   2-[(3′-methanesulfonylamino-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylic    acid,-   2-[(3′-dimethylaminosulfonylamino-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylic    acid,-   2-[(6-methoxy-3′-trifluoromethoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylic    acid,-   2-[(3′-cyanomethyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylic    acid,-   2-[(3′-isopropyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylic    acid,-   2-[(3′-chloro-6-methoxy-2′-methyl-biphenyl-3-carbonyl)-amino]-indane-2-carboxylic    acid,-   2-{[5-(3-chloro-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-indane-2-carboxylic    acid, and-   2-[3-(2,2-difluoro-2-phenyl-ethoxy)-4-methoxy-benzoylamino]-indane-2-carboxylic    acid,    or which is any one of these compounds, or a physiologically    acceptable salt thereof, or physiologically acceptable solvate of    any of them, wherein the compound of the formula I is a subject of    the invention in any of its stereoisomeric forms or a mixture of    stereoisomeric forms in any ratio where applicable.

As an example of compounds of the invention which with respect to anystructural elements are defined as in specified embodiments of theinvention or definitions of such elements, compounds of the formula Imay be mentioned wherein ring A is a cyclohexane ring, a benzene ring, apyridine ring, a pyridazine ring or a thiophene ring, wherein thecyclohexane ring is optionally substituted by one or more identical ordifferent substituents chosen from the series consisting of fluorine and(C₁-C₄)-alkyl, and the benzene ring, the pyridine ring, the pyridazinering and the thiophene ring are optionally substituted by one or moreidentical or different substituents chosen from the series consisting ofhalogen, R¹, HO—, R¹—O—, R¹—C(O)—O—, R¹—S(O)₂—O—, R¹—S(O)_(m)—, H₂N—,R¹—NH—, R¹—N(R¹)—, R¹—C(O)—NH—, R¹—C(O)—N(R⁷¹)—, R¹—S(O)₂—NH—,R¹—S(O)₂—N(R⁷¹)—, R¹—C(O)—, HO—C(O)—, R¹—O—C(O)—, H₂N—C(O)—,R¹—NH—C(O)—, R¹—N(R¹)—C(O)—, H₂N—S(O)₂—, R¹—NH—S(O)₂—, R¹—N(R¹)—S(O)₂—,NC— and O₂N—;

Y is chosen from the series consisting of S, C(R¹²)═C(R¹³), andC(R¹⁵)═N;

Z is C(R¹⁶);

and all other groups and numbers are defined as in the generaldefinition of the compounds of the formula I or in any specifiedembodiments of the invention or definitions of structural elements, inany of their stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, and their physiologically acceptable salts, and thephysiologically acceptable solvates of any of them.

As another such example compounds of the formula I may be mentioned,wherein ring A is a benzene ring, a pyridine ring, a pyrazine or athiophene ring which rings are all optionally substituted by one or twoidentical or different substituents chosen from the series consisting ofhalogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—;

Y is chosen from the series consisting of S, C(R¹²)═C(R¹³) and C(R¹⁵)═N;

Z is C(R¹⁶);

R³ and R⁵ are independently of each other chosen from the seriesconsisting of hydrogen and (C₁-C₄)-alkyl;R⁴ and R⁶ are hydrogen;R¹², R¹³, R¹⁵ and R¹⁶ are independently of each other chosen from theseries consisting of hydrogen, halogen (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—and NC—;R²⁰ is hydrogen;and all other groups and numbers are defined as in the generaldefinition of the compounds of the formula I or in any specifiedembodiments of the invention or definitions of structural elements, inany of their stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, and their physiologically acceptable salts, and thephysiologically acceptable solvates of any of them.

As another such example compounds of the formula I may be mentioned,wherein R²¹ is chosen from the series consisting of hydrogen, halogen,(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)_(m)—, H₂N—, (C₁-C₄)-alkyl-NH—, di((C₁-C₄)-alkyl)N—,(C₁-C₄)-alkyl-C(O)— and NC—;

R²² is a group of the formula II;

R²⁴—R²³—  II

R²³ is a direct bond or a chain consisting of 2, 3 or 4 chain members ofwhich 0 or 1 chain members are hetero chain members chosen from theseries consisting of N(R²⁵), O, S, S(O) and S(O)₂ and the other chainmembers are identical or different groups C(R²⁶)(R²⁶), wherein twoadjacent groups C(R²⁶)(R²⁶) can be connected to each other by a doublebond or a triple bond;and all other groups and numbers are defined as in the generaldefinition of the compounds of the formula I or in any specifiedembodiments of the invention or definitions of structural elements, inany of their stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, and their physiologically acceptable salts, and thephysiologically acceptable solvates of any of them.

As another such example compounds of the formula I may be mentioned,wherein R²⁴ is a 3-membered to 7-membered monocyclic ring or a7-membered to 10-membered bicyclic ring, which rings are saturated orunsaturated and contain 0, 1 or 2 identical or different hetero ringmembers chosen from the series consisting of N, N(R³²), O, S, S(O) andS(O)₂, and which rings are optionally substituted on ring carbon atomsby one or more identical or different substituents chosen from theseries consisting of halogen, R³³, HO—, R³³—O—, R³³—S(O)_(m)—, H₂N—,R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—, R³³—C(O)—N(R⁷¹)—, R³³—S(O)₂—NH—,R³³—S(O)₂—N(R⁷¹)—, H₂N—S(O)₂—NH—, R³³—NH—S(O)₂—NH—,R³³—N(R³³)—S(O)₂—NH—, H₂N—S(O)₂—N(R⁷¹)—, R³³—NH—S(O)₂—N(R⁷¹)—,R³³—N(R³³)—S(O)₂—N(R⁷¹)—, HO—C(O)—, R³³—O—C(O)—, H₂N—C(O)—,R³³—NH—C(O)—, R³³—N(R³³)—C(O)—, NC—, oxo, phenyl and Het;

R³² is chosen from the series consisting of hydrogen, R³⁵, R³⁵—C(O)—,R³⁵—O—C(O)— and phenyl;and all other groups and numbers are defined as in the generaldefinition of the compounds of the formula I or in any specifiedembodiments of the invention or definitions of structural elements, inany of their stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, and their physiologically acceptable salts, and thephysiologically acceptable solvates of any of them.

As another such example compounds of the formula I may be mentioned,wherein ring A is a benzene ring, a pyridine ring, a pyrazine or athiophene ring which rings are all optionally substituted by one or twoidentical or different substituents chosen from the series consisting ofhalogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—;

Y is chosen from the series consisting of S, C(R¹²)═C(R¹³) and C(R¹⁵)═N;

Z is C(R¹⁶);

R³ and R⁵ are independently of each other chosen from the seriesconsisting of hydrogen and (C₁-C₄)-alkyl;R⁴ and R⁶ are hydrogen;R¹², R¹³, R¹⁵ and R¹⁶ are independently of each other chosen from theseries consisting of hydrogen, halogen (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—and NC—;R²⁰ is hydrogen;R²¹ is chosen from the series consisting of hydrogen, halogen,(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)_(m)—, H₂N—, (C₁-C₄)-alkyl-NH—, di((C₁-C₄)-alkyl)N—,(C₁-C₄)-alkyl-C(O)— and NC—;R²² is a group of the formula II;

R²⁴—R²³—  II

R²³ is a direct bond or a chain consisting of 2, 3 or 4 chain members ofwhich 0 or 1 chain members are hetero chain members chosen from theseries consisting of N(R²⁵), O, S, S(O) and S(O)₂, and the other chainmembers are identical or different groups C(R²⁶)(R²⁶), wherein twoadjacent groups C(R²⁶)(R²⁶) can be connected to each other by a doublebond or a triple bond;R²⁴ is a 3-membered to 7-membered monocyclic ring or a 7-membered to10-membered bicyclic ring, which rings are saturated or unsaturated andcontains 0, 1 or 2 identical or different hetero ring members chosenfrom the series consisting of N, N(R³²), O, S, S(O) and S(O)₂, whichring is optionally substituted on ring carbon atoms by one or moreidentical or different substituents chosen from the series consisting ofhalogen, R³³, HO—, R³³—O—, R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—,R³³—C(O)—NH—, R³³—C(O)—N(R⁷¹)—, R³³—S(O)₂—NH—, R³³—S(O)₂—N(R⁷¹)—,HO—C(O)—, R³³—O—C(O)—, H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)—, NC—,oxo, phenyl and Het;R³² is chosen from the series consisting of hydrogen, R³⁵, R³⁵—C(O)—,R³⁵—O—C(O)— and phenyl;and all other groups and numbers are defined as in the generaldefinition of the compounds of the formula I or in any specifiedembodiments of the invention or definitions of structural elements, inany of their stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, and their physiologically acceptable salts, and thephysiologically acceptable solvates of any of them.

As another such example compounds of the formula I may be mentioned,wherein ring A is a benzene ring which is optionally substituted by oneor two identical or different substituents chosen from the seriesconsisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—;

Y is C(R¹²)═C(R¹³); Z is C(R¹⁶);

R³, R⁴, R⁵ and R⁶ are hydrogen;R¹², R¹³ and R¹⁶ are independently of each other chosen from the seriesconsisting of hydrogen, halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— andNC—;R²⁰ is hydrogen;R²¹ is chosen from the series consisting of hydrogen, halogen,(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)_(m)—, (C₁-C₄)-alkyl-C(O)— and NC—;R²² is a group of the formula II;

R²⁴—R²³—  II

R²³ is a direct bond or a chain consisting of 2, 3 or 4 chain members ofwhich 0 or 1 chain members are hetero chain members chosen from theseries consisting of N(R²⁵), O, S, S(O) and S(O)₂, and the other chainmembers are identical or different groups C(R²⁶)(R²⁶);R²⁴ is a benzene ring which is optionally substituted by one or moreidentical or different substituents chosen from the series consisting ofhalogen, R³³, HO—, R³³—O—, R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—,R³³—C(O)—NH—, R³³—S(O)₂—NH—, HO—C(O)—, R³³—O—C(O)—, H₂N—C(O)—,R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—; provided that the total numberof C, N, O and S atoms which is present in the two groups R²³ and R²⁴,is at least 5;R²⁵ is chosen from the series consisting of hydrogen and (C₁-C₄)-alkyl;R²⁶, independently of each other group R²⁶, is chosen from the seriesconsisting of hydrogen, fluorine, (C₁-C₄)-alkyl and HO—, or two of thegroups R²⁶ which are bonded to the same carbon atom in the chain,together with the carbon atom carrying them, form a cyclopropane ring;R³³ is, independently of each other group R³³, chosen from the seriesconsisting of (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, which are all optionally substitutedby one or more identical or different substituents R⁷⁰;R⁵⁰ is chosen from the series consisting of R⁵¹—O— and R⁵²—N(R⁵³)—;R⁵¹ is chosen from the series consisting of hydrogen and (C₁-C₄)-alkyl;R⁵² is chosen from the series consisting of hydrogen and (C₁-C₄)-alkyl;R⁵³ is chosen from the series consisting of hydrogen and (C₁-C₄)-alkyl;R⁷⁰ is chosen from the series consisting of HO— and R⁷¹—O—;R⁷¹ is (C₁-C₄)-alkyl;m, independently of each other number m, is an integer chosen from theseries consisting of 0 and 2;cycloalkyl, independently of each other group cycloalkyl, andindependently of any other substituents on cycloalkyl, is optionallysubstituted by one or more identical or different substituents chosenfrom fluorine and (C₁-C₄)-alkyl;alkyl, independently of each other group alkyl, and independently of anyother substituents on alkyl, is optionally substituted by one or morefluorine substituents; in any of their stereoisomeric forms or a mixtureof stereoisomeric forms in any ratio, and their physiologicallyacceptable salts, and the physiologically acceptable solvates of any ofthem.

Another subject of the present invention are processes for thepreparation of the compounds of the formula I which are outlined belowand by which the compounds are obtainable. For example, the preparationof the compounds of the formula I can be carried out by reacting acompound of the formula III with a compound of the formula IV withformation of an amide bond.

The ring A and the groups Y, Z, R³ to R⁶, R²⁰ to R²² and R⁵⁰ in thecompounds of the formulae III and IV are defined as in the compounds ofthe formula I and additionally functional groups can be present inprotected form or in the form of a precursor group which is laterconverted into the final group. The group G in the compounds of theformula IV can be HO— (hydroxy), i.e. the compound of the formula IV canthus be a carboxylic acid, or another group which can be replaced by thegroup N(R²⁰) in the compound of the formula III in a substitutionreaction, for example an aryloxy group such as optionally substitutedphenoxy or an alkyloxy group such as a (C₁-C₄)-alkyl-O— group, forexample a (C₁-C₃)-alkyl-O— group like methoxy or ethoxy, or halogen, forexample chlorine or bromine, and the compound of the formula IV can thusbe a reactive ester like an aryl ester or alkyl ester, for example amethyl ester or ethyl ester, or an acid halide, for example an acidchloride or acid bromide, of the respective carboxylic acid. Thecompound of the formula III and/or the compound of the formula IV canalso be employed, and the compounds of the formula I obtained, in theform of a salt, for example an acid addition salt such as anhydrohalide, for example a hydrochloride, of the compound of the formulaIII and/or an alkaline metal salt, for example a sodium salt, of acompound of the formula IV in which G is HO—. Likewise, in all otherreactions in the preparation of the compounds of the formula I,including the preparation of starting compounds, compounds can also beemployed and/or products obtained in the form a salt.

In case a compound of the formula IV is employed in which G is HO—, thecarboxylic acid group HO—C(O)— is generally activated in situ by meansof a customary amide coupling reagent or converted into a reactivecarboxylic acid derivative which can be prepared in situ or isolated.For example, the compound of the formula IV in which G is HO— can beconverted into an acid halide, e.g. the compound of the formula IV inwhich G is Cl or Br, by treatment with thionyl chloride, phosphoruspentachloride, phosphorus tribromide or oxalyl chloride, or treated withan alkyl chloroformate like ethyl chloroformate or isobutylchloroformate to give a mixed anhydride. Customary coupling reagentswhich can be employed, are propanephosphonic anhydride,N,N′-carbonyldiazoles like N,N′-carbonyldiimidazole (CD), carbodiimideslike 1,3-diisopropylcarbodiimide (DIC), 1,3-dicyclohexylcarbodiimide(DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC), carbodiimides together with additives like1-hydroxy-benzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT),uronium-based coupling reagents likeO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) orO-(cyano(ethoxycarbonyl)methyleneamino)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TOTU), and phosphonium-based coupling reagents like(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyBOP) or bromotripyrrolidinophosphoniumhexafluorophosphate (PyBroP).

The reaction conditions for the preparation of the compounds of theformula I from compounds of the formulae III and IV depend on theparticulars of the specific case, for example the meaning of the group Gor the employed coupling reagent, and are well known to a skilled personin view of the general knowledge in the art. For example, in case acompound of the formula IV in which G is alkyl-O—, like methoxy orethoxy, is reacted with a compound of the formula III, generally thereaction is carried out in an inert solvent, for example a hydrocarbonor chlorinated hydrocarbon like benzene, toluene, xylene, chlorobenzene,dichloromethane, chloroform or dichloroethane, an ether liketetrahydrofuran (THF), dioxane, dibutyl ether, diisopropyl ether ordimethoxyethane (DME), or a mixture of solvents, at elevatedtemperatures, for example at temperatures from about 40° C. to about140° C., in particular at temperatures from about 50° C. to about 120°C., for example at about the boiling temperature of the solvent. In casea compound of the formula IV in which G is halogen, like chlorine orbromine, is reacted with a compound of the formula III, generally thereaction is likewise carried out in an inert solvent, for example ahydrocarbon or chlorinated hydrocarbon or ether like the aforementionedones, an ester like ethyl acetate or butyl acetate, a nitrile likeacetonitrile, or water, or a mixture of solvents including a mixture ofwater and an organic solvent which is miscible or immiscible with water,at temperatures from about −10° C. to about 100° C., in particular attemperatures from about 0° C. to about 80° C., for example at about roomtemperature. Favorably, the reaction of a compound of the formula IV inwhich G is halogen with a compound of the formula III is carried out inthe presence of a base such as a tertiary amine, like triethylamine,ethyldiisopropylamine, N-methylmorpholine or pyridine, or an inorganicbase such as an alkaline metal hydroxide, carbonate orhydrogencarbonate, like sodium hydroxide, potassium hydroxide, sodiumcarbonate or sodium hydrogencarbonate.

In case a compound of the formula IV in which G is HO— is reacted with acompound of the formula III and the carboxylic acid group is activatedby means of an amide coupling reagent such as, for example, acarbodiimide or TOTU, the reaction is generally carried out underanhydrous conditions in an inert aprotic solvent, for example an etherlike THF, dioxane or DME, an amide like N,N-dimethylformamide (DMF) orN-methylpyrrolidone (NMP), at temperatures from about −10° C. to about40° C., in particular at temperatures from about 0° C. to about 30° C.in the presence of a base such as a tertiary amine, like triethylamine,ethyldiisopropylamine or N-methylmorpholine. In case the compound of theformula III is employed in the form of an acid addition salt in thereaction with the compound of the formula IV, usually a sufficientamount of a base is added in order to liberate the free compound of theformula III.

As indicated above, during the formation of the amide bond between thecompounds of the formulae III and IV functional groups in the compoundsof the formulae III and IV can be present in protected form or in theform of a precursor group. Depending on the particulars of the specificcase, it may be necessary or advisable for avoiding an undesired courseof the reaction or side reactions to temporarily block any functionalgroups by protective groups and remove them later, or to let functionalgroups be present in the form of a precursor group which is laterconverted into the desired final group. This applies correspondingly toall reactions in the course of the synthesis of the compounds of theformula I including the synthesis of intermediates outlined below andthe synthesis of starting compounds and building blocks. Respectivesynthetic strategies are commonly used in the art. Details aboutprotective groups and their introduction and removal are found in P. G.M. Wuts and T. W. Greene, Greene's Protective Groups in OrganicSynthesis, 4. ed. (2007), John Wiley & Sons, for example. Examples ofprotective groups which may be mentioned, are benzyl protective groupswhich may occur in the form of benzyl ethers of hydroxy groups andbenzyl esters of carboxylic acid groups from which the benzyl group canbe removed by catalytic hydrogenation in the presence of a palladiumcatalyst, tert-butyl protective groups which may occur in the form oftert-butyl esters of carboxylic acid groups from which the tert-butylgroup can be removed by treatment with trifluoroacetic acid, acylprotective groups which may be used to protect hydroxy groups and aminogroups in the form of esters and amides and which can be cleaved byacidic or basic hydrolysis, and alkyloxycarbonyl protective groups whichmay occur in the form of tert-butoxycarbonyl derivatives of amino groupswhich can be cleaved by treatment with trifluoroacetic acid. Undesiredreactions of carboxylic acid groups, for example the carboxylic acidgroup present in the compound of the formula III in case R⁵⁰ is HO—, canalso be avoided by employing them in the reaction of the compounds ofthe formulae III and IV in the form of other esters, for example in theform of alkyl esters like the methyl or ethyl ester which can be cleavedby hydrolysis, for example by means of an alkaline metal hydroxide likesodium hydroxide or lithium hydroxide. Examples of precursor groupswhich may be mentioned, are nitro groups which can be converted intoamino groups by catalytic hydrogenation or by reduction with sodiumdithionite, for example, and cyano groups (NC—, N≡C—) which can beconverted to carboxamide groups and carboxylic acid groups byhydrolysis. Another example of a precursor group is an oxo group whichrepresents the groups R³ and R⁴ together or the two groups R⁵ and R⁶together, and which may initially be present in the course of thesynthesis of compounds of the formula I in which R³ or R⁵ is hydroxy. Inan approach for the synthesis of such compounds of the formula I, acompound of the formula III in which the groups R³ and R⁴ together areoxo or the groups R⁵ and R⁶ together are oxo, may be obtained from therespective compound which contains a bromine atom instead of the groupR²⁰—NH— by reaction with sodium azide and subsequently with tributyl tinhydride as described in L. Benati et al., J. Org. Chem. 64 (1999),7836-7841, the obtained amino compound reacted with a compound of theformula IV, the oxo group reduced, for example with a complex hydridesuch as sodium borohydride, or reacted with an organometallic compound,for example a Grignard compound, and finally any protective groupsremoved. If any protective groups or precursor groups are present in thecompounds of the formulae III and IV and the direct product of thereaction of the compounds of the formulae III and IV is not yet thedesired final compound, the removal of the protective group orconversion into the desired compound can in general also be carried outin situ.

The compounds of the formula III are commercially available or can beobtained according to, or analogously to, procedures described in theliterature, for example by di-alkylation of an aminoacetic acidderivative of the formula VI with a compound of the formula Vanalogously as described in Kotha et al., J. Org. Chem. 65 (2000),1359-1365, for example.

The ring A and the groups R³ to R⁶ in the compound of the formula V aredefined as in the compounds of the formula I and additionally functionalgroups can be present in protected form or in the form of a precursorgroup which is later converted into the final group. The groups L¹ inthe alkylating compound of the formula V are leaving groups such ashalogen, for example chlorine or bromine, or sulfonyloxy groups, forexample methanesulfonyloxy or trifluoromethanesulfonyloxy. The group PG¹in the compound of the formula VI is a protective group of thecarboxylic acid group of aminoacetic acid and can be a group such as(C₁-C₄)-alkyl, for example methyl, ethyl or tert-butyl, or benzyl. Thegroup PG² in the compound of the formula VI is a divalent protectivegroup of the amino group of aminoacetic acid and can be a carbon atom,and the group —N═PG² thus be the isocyano group —N═C, or a carbon atomcarrying two phenyl groups, and the group —N═PG² thus be thebenzhydrylideneamino group —N═C(phenyl)₂, for example. The alkylationreaction of the compound of the formula VI with the compound of theformula V is carried out in the presence of base, for example analkaline metal alkoxide such as potassium tert-butoxide, or an alkalinemetal hydride such as sodium hydride, or an alkaline metal carbonatesuch as potassium carbonate with addition of a phase transfer catalystsuch as tetrabutylammonium hydrogensulfate under solid-liquid phasetransfer conditions, in an inert solvent such as an amide like DMF orNMP or a nitrile like acetonitrile at temperatures from about −40° C. toabout 80° C., depending on the particulars of the specific case.Subsequent to the alkylation, the protective group PG² is cleaved, forexample by treatment with hydrochloric acid in ethanol in the case of aisocyano group or with aqueous hydrochloric acid in the case of abenzhydrylideneamino group, optionally with concomitant cleavage of theprotective group PG¹, to give a compound of the formula III in which R⁵⁰is (C₁-C₄)-alkyl-O—, for example methoxy, ethoxy or tert-butoxy, orbenzyloxy, or HO—, and R²⁰ is hydrogen. Compounds of the formula III inwhich R²⁰ is different from hydrogen, can be obtained from the compoundsin which R²⁰ is hydrogen by alkylation or by acylation and subsequentreduction of the obtained amide to the amine. If desired, compounds ofthe formula III in which R⁵⁰ is HO— can be obtained by acidic or basichydrolysis from compounds in which R⁵⁰ is (C₁-C₄)-alkyl-O— or byhydrogenation from compounds in which R⁵⁰ is benzyloxy, for example.

The starting compounds of the formula V can be obtained from therespective dihydroxy compounds, which contain hydroxy groups instead ofthe groups L¹, by treatment with an halogenating agent, for examplethionyl chloride or phosphorus tribromide, or a sulfonylating agent suchas methanesulfonyl chloride or trifluoromethanesulfonic anhydride, orfrom the respective hydrocarbons which contain hydrogen atoms instead ofthe groups L¹, by benzylic bromination, for example withN-bromosuccinimide. The said dihydroxy compounds can be obtained fromthe respective dicarboxylic acids, which contain carboxylic acid groupsHO—C(O) instead of the groups L¹-C(R³)(R⁴)— and L¹-C(R⁵)(R⁶)—, oresterified carboxylic acid groups, by reduction, for example withlithium aluminium hydride, in case all groups R³ to R⁶ are hydrogen, orby reaction with an organometallic compound such as a Grignard compoundor an organolithium compound, for example methyl lithium, and optionallyby reduction, in case groups R³ to R⁶ are different from hydrogen.Compounds of the formula III in which A is a cycloalkane ring, canadditionally be obtained by hydrogenation in the presence of atransition metal hydrogenation catalyst such as a platinum catalyst, forexample, from the respective compounds in which ring A is an unsaturatedring, in particular in the case of compounds of the formula III in whichA is a cyclohexane ring which can be obtained from the respectivecompounds in which A is a benzene ring. In another approach, compoundsof the formula III can be obtained from the respective ketones, i.e. thecompounds of the formula III in which the two groups R²⁰—NH— andR⁵⁰—C(O)— are replaced with an oxo group, according to the classicalroutes for the synthesis of amino acids like the Strecker synthesis orthe Bucherer-Bergs synthesis. All said reactions are standard reactionswhich are well known to a person skilled in the art.

The compounds of the formula IV likewise are commercially available orcan be obtained according to, or analogously to, procedures described inthe literature. Customarily, in synthetic procedures for the preparationof compounds of the formula IV compounds are prepared in which the groupG in the compounds of the formula IV is a group like (C₁-C₄)-alkyl-O—and the group G-C(O)— thus is a (C₁-C₄)-alkyl ester group, or the groupG-C(O)— is any other ester group such as a benzyl esterphenyl-CH₂—O—C(O)— and the group G thus is a benzyloxy group. Compoundsof the formula IV in which G is HO—, can be obtained from such compoundsof the formula IV by acidic or basic hydrolysis of alkyl esters or byhydrogenation of benzyl esters under standard conditions. Compounds ofthe formula IV in which G is HO— can then be converted into compounds ofthe formula IV in which G is halogen as already explained above, whichlatter compounds can be converted into compounds in which G is aryloxy,for example by reaction with a hydroxyarene such as phenol. In thefollowing, various synthetic procedures for the preparation of compoundsof the formula IV in which the group R²³ in the group R²⁴—R²³—, i.e. inthe group of the formula II which represents one of the groups R²¹ andR²², has different meanings, are exemplarily outlined.

In a procedure for the preparation of compounds of the formula IV inwhich the group R²³ is a chain wherein the terminal chain member whichis bonded to the ring comprising the groups Y and Z, is a hetero chainmember, a compound of the formula VII is reacted with a compound of theformula VIII to give a compound of the formula IVa.

In the compounds of the formulae IVa, VII and VIII the groups Y, Z andR²⁴ are defined as in the compounds of the formula I. The group R⁸⁰ ischosen from the series consisting of hydrogen, halogen, R³⁰, HO—,R³⁰—O—, R³⁰—C(O)—O—, R³⁰—S(O)₂—O—, R³⁰—S(O)_(m)—, H₂N—, R³⁰—NH—,R³⁰—N(R³⁰)—, R³⁰—C(O)—NH—, R³⁰—C(O)—N(R⁷¹)—, R³⁰—S(O)₂—NH—,R³⁰—S(O)₂—N(R⁷¹)—, R³⁰—C(O)—, HO—C(O)—, R³⁰—O—C(O)—, H₂N—C(O)—,R³⁰—NH—C(O)—, R³⁰—N(R³⁰)—C(O)—, H₂N—S(O)₂—, R³⁰—NH—S(O)₂—,R³⁰—N(R³⁰)—S(O)₂—, NC—, O₂N— and Het¹; i.e. it has the meaning of theone of the groups R²¹ and R²² in the compounds of the formula I which isnot a group of the formula II. Additionally, functional groups in thecompounds of the formulae IVa, VII and VIII can be present in protectedform or in the form of a precursor group which is later converted intothe final group. The group G¹-C(O)— is an ester group and the group G¹ agroup such as (C₁-C₄)-alkyl-O— or benzyloxy. The group X is a heterochain member as specified in the definition of R²³, i.e. a group chosenfrom the series consisting of N(R²⁵), O, S, S(O) and S(O)₂, inparticular from the series consisting of N(R²⁵), O and S. The groupsR^(23a) and X together represent the group R²³ as specified abovewherein a terminal chain member which is a hetero chain member, isbonded to the ring comprising the groups Y and Z. R^(23a) thus is adirect bond or a chain consisting of 1 to 4 chain members of which 0 or1 chain member is a hetero chain member chosen from the seriesconsisting of N(R²⁵), O, S, S(O) and S(O)₂, provided that the terminalchain member adjacent to the group L² can only be a hetero chain memberwhich leads to the formation of compound of the formula IVa in which oneof the group X and the said terminal chain member is chosen from theseries consisting of S(O) and S(O)₂ and the other is chosen from theseries consisting of N(R²⁵), O and S, and the other chain members areidentical or different groups C(R²⁶)(R²⁶), wherein two adjacent groupsC(R²⁶)(R²⁶) can be connected to each other by a double bond or a triplebond. As is symbolized by the bonds connecting the groups R⁸⁰ and XH inthe compounds of the formula VII, as well as the groups R⁸⁰ andX—R^(23a)—R²⁴ in the compounds of the formula IVa, which bonds are notdirected to a specific ring carbon atom, each of the said two groups canbe located in each of the two positions of the moiety C═C in the ringcomprising the groups Y and Z which is depicted in the formulae. I.e.,R⁸⁰ can be located on the ring carbon which is adjacent to the group Yand the other of the two groups on the ring carbon atom which isadjacent to the group Z, as well as R⁸⁰ can be located on the ringcarbon which is adjacent to the group Z and the other of the two groupson the ring carbon atom which is adjacent to the group Y. This appliesto all compounds defined below containing a group R⁸⁰ and a second groupin which the bonds connecting the group to the ring comprising thegroups Y and Z are not directed to a specific ring carbon atoms. Thegroup L² in the compounds of the formula VIII is a leaving group whichcan be replaced with the group X, such as halogen, fore example chlorineor bromine, a sulfonyloxy group, for example methanesulfonyloxy,trifluoromethanesulfonyloxy or toluene-4-sulfonyloxy, or hydroxy, forexample.

The reaction of a compound of the formula VII with a compound of theformula VIII is a nucleophilic substitution reaction which can becarried out under standard conditions for such reactions which are wellknown to a person skilled in the art. Generally, the reaction isperformed in an inert solvent, for example a hydrocarbon or chlorinatedhydrocarbon like benzene, toluene, xylene, chlorobenzene,dichloromethane, chloroform or dichloroethane, an ether like THF,dioxane, dibutyl ether, diisopropyl ether or DME, an alcohol likemethanol, ethanol or isopropanol, a ketone like acetone or butan-2-one,an ester like ethyl acetate or butyl acetate, a nitrile likeacetonitrile, an amide like DMF or NMP, a sulfoxide like DMSO or asulfone like sulfolane, or a mixture of solvents, at temperatures fromabout −10° C. to about 120° C., in particular at temperatures from about0° C. to about 100° C., depending on the particulars of the specificcase. In many cases it is favorable for enhancing the nucleophilicity ofthe compound of the formula VII and/or binding an acid which isliberated during the reaction, to add a base, for example a tertiaryamine, such as triethylamine, ethyldiisopropylamine orN-methylmorpholine, or an inorganic base such as an alkaline metalhydride, hydroxide, carbonate or hydrogencarbonate like sodium hydride,sodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate, cesium carbonate or sodium hydrogencarbonate, or an alkoxideor amide such as sodium methoxide, sodium ethoxide, potassium methoxide,potassium tert-butoxide, sodium amide or lithium diisopropylamide. Acompound of the formula VII can also be treated with a base andconverted into a salt in a separate step. Compounds of the formula VIIIin which the group L² is hydroxy can favorably be reacted with compoundsof the formula VII under the conditions of the Mitsunobu reaction in thepresence of an azodicarboxylate like diethyl azodicarboxylate ordiisopropyl azodicarboxylate and a phosphine like triphenylphosphine ortributylphosphine in an inert aprotic solvent such as an ether like THFor dioxane (cf. O. Mitsunobu, Synthesis (1981), 1-28).

In another procedure, compounds of the formula IVa can be obtained byreacting a compound of the formula IX with a compound of the formula X.

In the compounds of the formulae IX and X the groups Y, Z and R²⁴ aredefined as in the compounds of the formula I. The group R⁸⁰ is definedas in the compounds of the formulae IVa and VII, i.e. it has the meaningof the one of the groups R²¹ and R²² in the compounds of the formula Iwhich is not a group of the formula II. Additionally, functional groupsin the compounds of the formulae IX and X can be present in protectedform or in the form of a precursor group which is later converted intothe final group. The group G¹-C(O)— is an ester group and the group G¹ agroup such as (C₁-C₄)-alkyl-O— or benzyloxy. The group X is a heterochain member as specified in the definition of R²³, i.e. a group chosenfrom the series consisting of N(R²⁵), O, S, S(O) and S(O)₂, inparticular from the series consisting of N(R²⁵), O and S. In thecompound of the formula X the groups R^(23a) and X together representthe group R²³ as specified above wherein a terminal chain member whichis a hetero chain member, is bonded to the ring comprising the groups Yand Z in the obtained compounds of the formula IVa. R^(23a) thus is adirect bond or a chain consisting of 1 to 4 chain members of which 0 or1 chain member is a hetero chain member chosen from the seriesconsisting of N(R²⁵), O, S, S(O) and S(O)₂, provided that the terminalchain member adjacent to the group X can only be a hetero chain memberif one of the group X and the said terminal chain member is chosen fromthe series consisting of S(O) and S(O)₂ and the other is chosen from theseries consisting of N(R²⁵), O and S, and the other chain members areidentical or different groups C(R²⁶)(R²⁶), wherein two adjacent groupsC(R²⁶)(R²⁶) can be connected to each other by a double bond or a triplebond. The group L³ in the compounds of the formulae IX is a leavinggroup which can be replaced with the group X, such as halogen likefluorine, chlorine, bromine or iodine, or a sulfonyloxy group likemethanesulfonyloxy or trifluoromethanesulfonyloxy, for example. Thereaction of a compound of the formula IX with a compound of the formulaX formally is a nucleophilic substitution reaction at the ringcomprising the groups Y and Z which can in particular be performed incase of compounds of the formulae IX which are susceptible to such areaction because of the presence of electron-withdrawing substituents orring hetero atoms. The reaction can be carried out under standardconditions for such reactions which are well known to a person skilledin the art. The explanations on the reaction conditions such as solventsor bases which are favorably added, which are given above with respectto the reaction of a compound of the formula VII with a compound of theformula VIII apply correspondingly to the reaction of a compound of theformula IX with a compound of the formula X.

The explanations on the reaction of a compound of the formula VII with acompound of the formula VIII also apply correspondingly to reactions forthe preparation of compounds of the formula I in which a hetero chainmember in the group R²³ is not present in the terminal position of thechain which is adjacent to the ring comprising the groups Y and Z, butis separated from the said ring by one or more groups C(R²⁶)(R²⁶), whichreactions are of the same type as the reactions outlined above. As anexample, the preparation of a compound of the formula IVb from acompound of the formula XI and a compound of the formula XII may beillustrated.

In the compounds of the formulae IVb, XI and XII the groups Y, Z and R²⁴are defined as in the compounds of the formula I. The group R⁸⁰ isdefined as in the compounds of the formulae IVa and VII, i.e. it has themeaning of the one of the groups R²¹ and R²² in the compounds of theformula I which is not a group of the formula II. Additionally,functional groups in the compounds of the formulae IX and X can bepresent in protected form or in the form of a precursor group which islater converted into the final group. Additionally, functional groups inthe compounds of the formulae IVb, XI and XII can be present inprotected form or in the form of a precursor group which is laterconverted into the final group. The group G¹-C(O)— is an ester group andthe group G¹ a group such as (C₁-C₄)-alkyl-O— or benzyloxy. The group Xis a hetero chain member as specified in the definition of R²³, i.e. agroup chosen from the series consisting of N(R²⁵), O, S, S(O) and S(O)₂,in particular from the series consisting of N(R²⁵), O and S. The groupsR^(23b), R^(23c) and X in the compounds of the formulae IVb togetherrepresent the group R²³ as specified above wherein X is a said heterochain member. In case R²³ comprises only one hetero chain member, thegroup R^(23b) in the compounds of the formulae IVb and XI is a chainconsisting of 1 to 4 identical or different groups C(R²⁶)(R²⁶) and thegroup R^(23c) in the compounds of the formulae IVb and XII is a directbond or a chain consisting of 1 to 3 identical or different groupsC(R²⁶)(R²⁶), provided that the total number of groups C(R²⁶)(R²⁶) is notgreater than 4, wherein two adjacent groups C(R²⁶)(R²⁶) can be connectedto each other by a double bond or a triple bond. In the group R^(23c) inthe compounds of the formulae IVb and XII a further hetero chain memberchosen from the series consisting of N(R²⁵), O, S, S(O) and S(O)₂ can bepresent instead of one of the groups C(R²⁶)(R²⁶), provided that suchfurther hetero chain member can only be present in the terminal positionadjacent to the group L² if one of the group X and the said chain memberin the terminal position is chosen from the series consisting of S(O)and S(O)₂ and the other is chosen from the series consisting of N(R²⁵),O and S. The leaving group L² in the compounds of the formula XII isdefined as in the compounds of the formula VIII. Correspondingly asoutlined above with respect to the synthesis of the compounds of theformula IVa, which can be prepared by reacting a compound of the formulaVII with a compound of the formula VIII as well as by reacting acompound of the formula IX with a compound of the formula X, compoundsof the formula IVb can also be prepared by reacting a compound which isdefined as the compound of the formula XI but contains a group L²instead of the group XH, with a compound which is defined as thecompound of the formula XII but contains a group XH instead of the groupL².

In a procedure for the preparation of compounds of the formula IV inwhich the group R²³ is a chain which does not comprise any hetero chainmember, a carbonyl compound of the formula XIII is condensed with acompound of the formula XIV to give an olefin of the formula IVc whichcan subsequently be hydrogenated to give a compound of the formula IVd,respectively, or reacted with an organometallic compound of the formulaXV to give an alcohol of the formula IVe which likewise can subsequentlybe hydrogenated to give a compound of the formula IVf.

In the compounds of the formulae IVc to IVf, XIII, XIV and XV the groupsY, Z and R²⁴ are defined as in the compounds of the formula I. The groupR⁸⁰ is defined as in the compounds of the formulae IVa and VII, i.e. ithas the meaning of the one of the groups R²¹ and R²² in the compounds ofthe formula I which is not a group of the formula II. Additionally,functional groups in the compounds of the formulae IVc to IVf, XIII, XIVand XV can be present in protected form or in the form of a precursorgroup which is later converted into the final group. The group G¹-C(O)—is an ester group and the group G¹ a group such as (C₁-C₄)-alkyl-O— orbenzyloxy. The groups R^(a) and R^(b) are independently of each otherchosen from hydrogen and (C₁-C₄)-alkyl. The group R^(23d) is a directbond or a chain consisting of 1 to 3 identical or different groupsC(R²⁶)(R²⁶), the group R^(23e) a direct bond or a chain consisting of 1to 4 identical or different groups C(R²⁶)(R²⁶). The group L⁴ in thecompounds of the formula XIV is group which allows for the formation ofa double bond between the carbon atom carrying the group L⁴ and thecarbon atom of the aldehyde group or ketone group carrying the groupR^(a) in the compound of the formula XIII in a condensation reaction.Examples of suitable condensation reactions are the Wittig reaction andthe Wittig-Horner reaction, and examples of suitable groups L⁴ thus aretrisubstituted phosphonio groups, such as the triphenylphosphonio group,having an anion, such as a halide anion, as counterion, anddi((C₁-C₄)-alkyl)phosphonyl groups, such as the diethylphosphonyl group.The group L⁵ in the compounds of the formula XV is a metal such aslithium or a magnesium halide group like MgCl, MgBr or MgI, and thecompound of the formula XV thus an organolithium compound or a Grignardcompound. The Wittig reaction and Wittig-Horner reaction and theaddition of the organometallic compound of the formula XV to thecompound of the formula XIII can be performed under standard conditionsin an inert solvent such as a hydrocarbon like benzene or toluene or anether like diethyl ether, THF, dioxane or DME. The Wittig reaction andthe Wittig-Horner reaction are performed in the presence of a base suchas a hydride like sodium hydride, an amide like sodium amide or lithiumdiisopropylamide, or an alkoxide like potassium tert-butoxide. Dependingon the particular case, instead of employing a phosphonium salt anddeprotonating it, also stable phosphorus ylides can directly be employedin the reaction. The hydrogenation of the double bond in the compoundsof the formula IVc to give the compounds of the formulae IVd, or of thebenzylic hydroxy group in the compounds of the formulae IVe to give thecompounds of the formulae IVf, can be performed in the presence of ahydrogenation catalyst such as palladium on charcoal.

Depending on the particulars of the specific case, various otherreactions can be used for preparing compounds of the formula IV. As anexample of the preparation of compounds in which the group R²³ is achain comprising three groups C(R²⁶)(R²⁶) and no hetero chain members,an aldol-type reaction of a compound of the formula XIIIa, which is acompound of the formula XIII in which the group R^(a) is methyl, with analdehyde of the formula XVI may be mentioned which leads to a compoundof the formula IVg or the formula IVm which can be reduced to a compoundof the formula IVh, IVk or IVn, for example.

In the compounds of the formulae IVg to IVn and XIIIa the groups Y and Zare defined as in the compounds of the formula I. The group R^(24a) inthe compounds of the formulae IVg to IVn and XVI is a group R³¹ or a3-membered to 10-membered ring as it can represent the group R²⁴ in thecompounds of the formula I which is bonded via a ring carbon atom, inparticular an aromatic ring such as an optionally substituted phenyl,naphthyl or heteroaryl group. The group R⁸⁰ is defined as in thecompounds of the formulae IVa and VII, i.e. it has the meaning of theone of the groups R²¹ and R²² in the compounds of the formula I which isnot a group of the formula II. Additionally, functional groups in thecompounds of the formulae IVg to IVn, XIIIa and XVI can be present inprotected form or in the form of a precursor group which is laterconverted into the final group. The group G¹-C(O)— is an ester group andthe group G¹ a group such as (C₁-C₄)-alkyl-O— or benzyloxy.

The reaction of a compound of the formula XIIIa with a compound of theformula XIV to give an aldol addition product of the formula IVm or acondensation product of the formula IVg can be carried under standardconditions for the aldol reaction in the presence of a base, such as analkaline metal hydroxide like sodium hydroxide or potassium hydroxide,an alkoxide like sodium methoxide or sodium ethoxide or an amide likelithium diisopropylamide, in a solvent such as an alcohol like methanolor ethanol or an ether like diethyl ether, THF or dioxane. At lowertemperatures, for example at temperatures from about −80° C. to about−30° C., the compound of the formula IVm can be obtained, at highertemperatures, for example at temperatures from about 10° C. to about 60°C., or by treatment of the compound of the formula IVm with an acid, thecompound of the formula IVg can be obtained. The ketone function in thecompounds of the formulae IVg and IVm can be reduced to an alcoholfunction, for example with a complex hydride such as a borohydride likelithium borohydride or sodium borohydride, to give a compound of theformula IVh or IVn, respectively, which can be converted into a compoundof the formula IVk by dehydration in the presence of an acid and/orhydrogenation in the presence of a catalyst such as palladium oncharcoal, for example.

As a further example of reactions which can be used for preparingcompounds of the formula IV, transition metal-catalyzed C—C couplingreactions may be mentioned by which compounds can be obtained whereinthe group R²³ is a direct bond or comprises a chain of two groupsC(R²⁶)(R²⁶), which are connected to each other by a triple bond, i.e. agroup of the formula —C≡C—, in a position adjacent to the ringcomprising the groups Y and Z. Such compounds can be obtained from acompound of the formula IX and a boronic acid, for example an optionallysubstituted phenylboronic acid, cycloalkylboronic acid orheteroarylboronic acid, or an ethyne, for example an optionallysubstituted phenylethyne. As catalyst in such reactions, a palladiumcompound such as bis(triphenylphosphine)palladium(II) chloride ortetrakis(triphenylphosphine)palladium(0) and a copper compound such ascopper(I) iodide can be used. Further details on such reactions arefound in N. Miyaura et al., Chem. Rev. 95 (1995), 2457-2483; and R.Chinchilla et al., Chem. Rev. 107 (2007), 874-922, for example.

The order in which groups are introduced in the course of the synthesisof a compound of the formula I, can also be different from the onesoutlined above. For example, instead of first preparing a compound ofthe formula IVa from a compound of the formula VII and a compound of theformula VIII, or from a compound of the formula IX and a compound of theformula X, and then reacting the compound of the formula IVa with acompound of the formula III to give a compound of the formula I, acompound of the formula III can also be reacted with a compound of theformula VII or a compound of the formula IX and the obtained compound ofthe formula XVII or XVIII reacted with a compound of the formula VIII orX, respectively, to give a compound of the formula Ik.

In the compounds of the formulae Ik, XVII and XVIII the ring A and thegroups Y, Z, R³ to R⁶, R²⁰, R²⁴ and R⁵⁰ are defined as in the compoundsof the formula I. The groups X, R^(23a) and R⁸⁰ are defined as in thecompounds of the formula IVa. Thus, R⁸⁰ has the meaning of the one ofthe groups R²¹ and R²² in the compounds of the formula I which is not agroup of the formula II. The group X is a hetero chain member asspecified in the definition of R²³, i.e. a group chosen from the seriesconsisting of N(R²⁵), O, S, S(O) and S(O)₂, in particular from theseries consisting of N(R²⁵), O and S. The groups R^(23a) and X togetherrepresent the group R²³ as specified above wherein a terminal chainmember which is a hetero chain member, is bonded to the ring comprisingthe groups Y and Z. R^(23a) thus is a direct bond or a chain consistingof 1 to 4 chain members of which 0 or 1 chain member is a hetero chainmember chosen from the series consisting of N(R²⁵), O, S, S(O) andS(O)₂, provided that the terminal chain member adjacent to the group Xcan only be a hetero chain member if one of the group X and the saidterminal chain member is chosen from the series consisting of S(O) andS(O)₂ and the other is chosen from the series consisting of N(R²⁵), Oand S, and the other chain members are identical or different groupsC(R²⁶)(R²⁶), wherein two adjacent groups C(R²⁶)(R²⁶) can be connected toeach other by a double bond or a triple bond. Additionally, functionalgroups in the compounds of the formulae Ik, XVII and XVIII can bepresent in protected form or in the form of a precursor group which islater converted into the final group. As indicated above and as appliesto all compounds which contain a group R⁸⁰ and another group which areconnected to the ring comprising the groups Y and Z by bonds which arenot directed to a specific ring carbon atom, the groups R⁸⁰ and X in thecompounds of the formula XVII, the groups R⁸⁰ and L³ in the compounds ofthe formula XVIII, and the groups R⁸⁰ and X—R^(23a)—R²⁴ in the compoundsof the formula Ik can be located in each of the two positions of themoiety C═C in the ring comprising the groups Y and Z. The explanationsgiven above with respect to the reaction of a compound of the formulaIII with a compound of the formula IV, the reaction of a compound of theformula VII with a compound of the formula VIII, and the reaction of acompound of the formula IX with a compound of the formula X applycorrespondingly to the reaction of a compound of the formula III with acompound of the formula VII or a compound of the formula IX, thereaction of a compound of the formula XVII with a compound of theformula VIII, and the reaction of a compound of the formula XVIII with acompound of the formula X. The order in which groups are introduced inthe course of the synthesis of a compound of the formula I, can also bevaried with respect to other reactions. For example, a compound of theformula XVIII can be employed in a transition-metal catalyzed C—Ccoupling reaction as referred to above, or a compound of the formulaXIIIa can be reacted with a compound of the formula III and the obtainedcompound modified at the CH₃—C(O)— group to give a compound of theformula I.

The starting compounds and building blocks for the synthesis of thecompounds of the formula I are commercially available or can be preparedaccording to procedures described in the literature or analogously tosuch procedures. Exemplarily the preparation of compounds of the formulaVIII in which R²⁴ is an optionally substituted phenyl or naphthyl group,R^(23a) is an optionally alkyl-substituted CH₂CH₂ group and L² is ahydroxy group, may be mentioned in which use can be made of theprocedure for the coupling of aryl halides with ester enolates describedby M. Jorgensen et al., J. Am. Chem. Soc. 124 (2002), 12557-12565. Inthe said procedure an optionally alkyl-substituted acetic acid ester,for example acetic acid tert-butyl ester or isobutyric acid methylester, is deprotonated with a base such as lithium dicyclohexylamide andreacted with an optionally substituted aryl bromide in the presence of apalladium compound such as bis(dibenzylideneacetone)palladium ortris(dibenzylideneactone)dipalladium and tri(tert-butyl)phosphine togive a 2-(optionally substituted aryl)acetic acid ester which isoptionally alkyl-substituted in the 2-position of the acetic acidmoiety. Reduction of the ester function under standard conditions, forexample with lithium aluminium hydride, then affords the 2-(optionallysubstituted aryl)ethanol which is optionally alkyl-substituted in the2-position.

For obtaining further compounds of the formula I, varioustransformations of functional groups can be carried out under standardconditions in compounds of the formula I or intermediates or startingcompounds in the synthesis of the compounds of the formula I. Forexample, a hydroxy group can be esterified to give a carboxylic acidester or a sulfonic acid ester, or etherified. Etherifications ofhydroxy groups can favorably be performed by alkylation with therespective halogen compound, for example a bromide or iodide, in thepresence of a base such an alkali metal carbonate like potassiumcarbonate or cesium carbonate in an inert solvent such as an amide likeDMF or NMP or a ketone like acetone or butan-2-one, or with therespective alcohol under the conditions of the Mitsunobu reactionreferred to above. A hydroxy group can be converted into a halide bytreatment with a halogenating agent. A halogen atom can be replaced witha variety of groups in a substitution reaction which may also be atransition-metal catalyzed reaction. A nitro group can be reduced to anamino group, for example by catalytic hydrogenation. An amino group canbe modified under standard conditions for alkylation, for example byreaction with a halogen compound or by reductive amination of a carbonylcompound, or for acylation or sulfonylation, for example by reactionwith an activated carboxylic acid or a carboxylic acid derivate like anacid chloride or anhydride or a sulfonic acid chloride. A carboxylicester group can be hydrolyzed under acidic or basic conditions to give acarboxylic acid. A carboxylic acid group can be activated or convertedinto a reactive derivative as outlined above with respect to thecompounds of the formula IX and reacted with an alcohol or an amine orammonia to give an ester or amide. A primary amide can be dehydrated togive a nitrile. A sulfur atom in an alkyl-S— group or in a heterocyclicring or a sulfur atom occurring in a chain representing the group R²³can be oxidized with a peroxide like hydrogen peroxide or a peracid togive a sulfoxide moiety S(O) or a sulfone moiety S(O)₂. A carboxylicacid group, carboxylic acid ester group and a ketone group can bereduced to an alcohol, for example with a complex hydride such allithium aluminium hydride, lithium borohydride or sodium borohydride.All reactions in the preparation of the compounds of the formula I areknown per se and can be carried out in a manner familiar to a personskilled in the art according to, or analogously, to procedures which aredescribed in the standard literature, for example in Houben-Weyl,Methods of Organic Chemistry, Thieme; or Organic Reactions, John Wiley &Sons; or R. C. Larock, Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2. ed. (1999), John Wiley & Sons, and thereferences quoted therein. Furthermore, besides by techniques ofsolution chemistry, the compounds of the formula I can also be obtainedby solid phase chemistry.

Another subject of the present invention are the novel startingcompounds and intermediates occurring in the synthesis of the compoundsof the formula I, including the compounds of the formulae III, IV, IV,IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVk, IVm, IVn, V, VI, VII, VIII, IX,X, XI, XII, XIII, XIV, XV, XVI, XVII and XVIII, wherein the ring A andthe groups G, G¹, L¹, L², L³, PG¹, PG², X, Y, Z, R³ to R⁶, R²⁰ to R²³,R^(23a), R^(23b), R^(23c), R²⁴, R^(24a), R⁵⁰, R⁸⁰, R^(a) and R^(b) aredefined as above, in any of their stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, and their salts, and solvates of anyof them, and their use as synthetic intermediates or starting compounds.All general explanations, specifications of embodiments and definitionsof numbers and groups given above with respect to the compounds of theformula I apply correspondingly to the said intermediates and startingcompounds. A subject of the invention are in particular the novelspecific starting compounds and intermediates described herein.Independently thereof whether they are described as a free compoundand/or as a specific salt, they are a subject of the invention both inthe form of the free compounds and in the form of their salts, and if aspecific salt is described, additionally in the form of this specificsalt.

The compounds of the formula I inhibit the Edg-2 receptor (LPA₁receptor) as can be demonstrated in the pharmacological test describedbelow and in other tests which are known to a person skilled in the art.The compounds of the formula I and their physiologically acceptablesalts and solvates therefore are valuable pharmaceutical activecompounds. The compounds of the formula I and their physiologicallyacceptable salts and solvates can be used for the treatment ofcardiovascular diseases such as heart failure including systolic heartfailure, diastolic heart failure, diabetic heart failure and heartfailure with preserved ejection fraction, cardiomyopathy, myocardialinfarction, myocardial remodeling including myocardial remodeling afterinfarction or after cardiac surgery, vascular remodeling includingvascular stiffness, hypertension including pulmonary hypertension,portal hypertension and systolic hypertension, atherosclerosis,peripheral arterial occlusive disease (PAOD), restenosis, thrombosis orvascular permeability disorders, for cardioprotection such ascardioprotection after myocardial infarction or after cardiac surgery,for renoprotection, or for the treatment of inflammation or inflammatorydiseases such as rheumatoid arthritis, osteoarthritis, renal diseasessuch as renal papillary necrosis or renal failure including renalfailure after ischemia/reperfusion, pulmonary diseases such as chronicobstructive pulmonary disease (COPD), asthma or acute respiratorydystress syndrome (ARDS), immunological diseases, allergic diseases,tumor growth, metastasis, metabolic diseases, fibrotic diseases such aspulmonary fibrosis including idiopathic lung fibrosis, cardiac fibrosis,vascular fibrosis, perivascular fibrosis, renal fibrosis including renaltubulointerstitial fibrosis, liver fibrosis, fibrosing skin conditionsincluding keloid formation, collagenosis, scleroderma, progressivesystemic sclerosis and nephrogenic fibrosing dermopathy, or other typesof fibrosis including Dupuytren's contracture, psoriasis, pain such asneuropathic pain, diabetic pain or inflammatory pain, pruritus, retinalischemia/reperfusion damage, macular degeneration, psychiatricdisorders, neurodegenerative diseases, cerebral nerve disorders,peripheral nerve disorders, endocrinic disorders such ashyperthyroidism, scarring disorders or wound healing disorders, forexample. The treatment of diseases is to be understood as meaning boththe therapy of existing pathological changes or malfunctions of theorganism or of existing symptoms with the aim of relief, alleviation orcure, and the prophylaxis or prevention of pathological changes ormalfunctions of the organism or of symptoms in humans or animals whichare susceptible thereto and are in need of such a prophylaxis orprevention, with the aim of a prevention or suppression of theiroccurrence or of an attenuation in the case of their occurrence. Forexample, in patients who on account of their disease history aresusceptible to myocardial infarction, by means of the prophylactic orpreventive medicinal treatment the occurrence or re-occurrence of amyocardial infarction can be prevented or its extent and sequelaedecreased, or in patients who are susceptible to disturbed woundhealing, by means of the prophylactic or preventive medicinal treatmentwound healing after surgery can favorably be influenced. The treatmentof diseases can occur both in acute cases and in chronic cases. Theefficacy of the compounds of the formula I can be demonstrated in thepharmacological tests described below and in other tests which are knownto a person skilled in the art

The compounds of the formula I and their physiologically acceptablesalts and solvates can therefore be used in animals, in particular inmammals and specifically in humans, as a pharmaceutical or medicament ontheir own, in mixtures with one another or in the form of pharmaceuticalcompositions. A subject of the present invention also are the compoundsof the formula I and their physiologically acceptable salts and solvatesfor use as a pharmaceutical, as well as pharmaceutical compositions andmedicaments which comprise an efficacious dose of at least one compoundof the formula I and/or a physiologically acceptable salt thereof and/orsolvate thereof as an active ingredient and a pharmaceuticallyacceptable carrier, i.e. one or more pharmaceutically innocuous, ornonhazardous, vehicles and/or excipients, and optionally one or moreother pharmaceutical active compounds. A subject of the presentinvention furthermore are the compounds of the formula I and theirphysiologically acceptable salts and solvates for use in the treatmentof the diseases mentioned above or below, including the treatment of anyone of the mentioned diseases, for example heart failure or fibroticdiseases such as pulmonary fibrosis, cardiac fibrosis, vascularfibrosis, perivascular fibrosis, renal fibrosis, liver fibrosis orfibrosing skin conditions, the use of the compounds of the formula I andtheir physiologically acceptable salts and solvates for the manufactureof a medicament for the treatment of the diseases mentioned above orbelow, including the treatment of any one of the mentioned diseases, forexample heart failure or fibrotic diseases such as pulmonary fibrosis,cardiac fibrosis, vascular fibrosis, perivascular fibrosis, renalfibrosis, liver fibrosis or fibrosing skin conditions, wherein thetreatment of diseases comprises their therapy and prophylaxis asmentioned above, as well as their use for the manufacture of amedicament for the inhibition of the Edg-2 receptor (LPA₁ receptor). Asubject of the invention also are methods for the treatment of thediseases mentioned above or below, including the treatment of any one ofthe mentioned diseases, for example heart failure or fibrotic diseasessuch as pulmonary fibrosis, cardiac fibrosis, vascular fibrosis,perivascular fibrosis, renal fibrosis, liver fibrosis or fibrosing skinconditions, which comprise administering an efficacious amount of atleast one compound of the formula I and/or a physiologically acceptablesalt thereof and/or solvate thereof to a human or an animal which is inneed thereof. The compounds of the formula I and pharmaceuticalcompositions and medicaments comprising them can be administeredenterally, for example by oral, sublingual or rectal administration,parenterally, for example by intravenous, intramuscular, subcutaneous orintraperitoneal injection or infusion, or by another type ofadministration such as topical, percutaneous, transdermal,intra-articular, intranasal or intraocular administration.

The compounds of the formula I and their physiologically acceptablesalts and solvates can also be used in combination with otherpharmaceutical active compounds, wherein in such a combination use thecompounds of the formula I and/or their physiologically acceptable saltsand/or solvates and one or more other pharmaceutical active compoundscan be present in one and the same pharmaceutical composition or in twoor more pharmaceutical compositions for separate, simultaneous orsequential administration. Examples of such other pharmaceutical activecompounds are angiotensin converting enzyme (ACE) inhibitors, ramipril,angiotensin II receptor subtype 1 (AT1) antagonists, irbesartan,antiarrhythmics, dronedarone, peroxisome proliferator-activatedreceptor-alpha (PPAR-α) activators, peroxisome proliferator-activatedreceptor-gamma (PPAR-γ) activators, pioglitazone, rosiglitazone,prostanoids, endothelin receptor antagonists, bosentan, elastaseinhibitors, calcium antagonists, beta blockers, diuretics, aldosteronereceptor antagonists, eplerenone, renin inhibitors, rho kinaseinhibitors, soluble guanylate cyclase (sGC) activators, sGC sensitizers,phosphodiesterase (PDE) inhibitors, phosphodiesterase type 5 (PDE5)inhibitors, NO donors, digitalis drugs, angiotensin convertingenzyme/neutral endopeptidase (ACE/NEP) inhibitors, statins, bile acidreuptake inhibitors, platelet derived growth factor (PDGF) receptorantagonists, vasopressin antagonists, aquaretics, sodium hydrogenexchanger subtype 1 (NHE1) inhibitors, factor II/factor IIa antagonists,factor IX/factor IXa antagonists, factor X/factor Xa antagonists, factorXIII/factor XIIIa antagonists, anticoagulants, antithrombotics, plateletinhibitors, profibrinolytics, thrombin-activatable fibrinolysisinhibitors (TAFI), plasminogen activator inhibitor-1 (PAI 1), coumarins,heparins, thromboxane antagonists, serotonin antagonists, cyclooxygenaseinhibitors, acetylsalicylic acid, therapeutic antibodies, glycoproteinIIb/IIIa (GPIIb/IIIa) antagonists including abciximab, chymaseinhibitors, cytostatics, taxanes, paclitaxel, docetaxel, aromataseinhibitors, estrogen receptor antagonists, selective estrogen receptormodulators (SERM), tyrosine kinase inhibitors, imatinib, receptortyrosine kinase inhibitors, RAF kinase inhibitors, p38 mitogen-activatedprotein kinase (p38 MAPK) inhibitors, pirfenidone, multi-kinaseinhibitors, and sorafenib. A subject of the present invention also isthe said combination use of any one or more of the compounds of theformula I disclosed herein and their physiologically acceptable saltsand solvates, with any one or more, for example one or two, of thementioned other pharmaceutical active compounds.

The pharmaceutical compositions and medicaments according to theinvention normally contain from about 0.5 to about 90 percent by weightof compounds of the formula I and/or physiologically acceptable saltsand/or solvates thereof, and an amount of active ingredient of theformula I and/or its physiologically acceptable salt and/or solvatewhich in general is from about 0.2 mg to about 1000 mg, in particularfrom about 0.2 mg to about 500 mg, for example from about 1 mg to about300 mg, per unit dose. Depending on the kind of the pharmaceuticalcomposition and other particulars of the specific case, the amount maydeviate from the indicated ones. The production of the pharmaceuticalcompositions and medicaments can be carried out in a manner known perse. For this, the compounds of the formula I and/or theirphysiologically acceptable salts and/or solvates are mixed together withone or more solid or liquid vehicles and/or excipients, if desired alsoin combination with one or more other pharmaceutical active compoundssuch as those mentioned above, and brought into a suitable form fordosage and administration, which can then be used in human medicine orveterinary medicine.

As vehicles, which may also be looked upon as diluents or bulkingagents, and excipients suitable organic and inorganic substances can beused which do not react in an undesired manner with the compounds of theformula I. As examples of types of excipients, or additives, which canbe contained in the pharmaceutical compositions and medicaments,lubricants, preservatives, thickeners, stabilizers, disintegrants,wetting agents, agents for achieving a depot effect, emulsifiers, salts,for example for influencing the osmotic pressure, buffer substances,colorants, flavorings and aromatic substances may be mentioned. Examplesof vehicles and excipients are water, vegetable oils, waxes, alcoholssuch as ethanol, isopropanol, 1,2-propanediol, benzyl alcohols,glycerol, polyols, polyethylene glycols or polypropylene glycols,glycerol triacetate, polyvinylpyrrolidone, gelatin, cellulose,carbohydrates such as lactose or starch like corn starch, sodiumchloride, stearic acid and its salts such as magnesium stearate, talc,lanolin, petroleum jelly, or mixtures thereof, for example saline ormixtures of water with one or more organic solvents such as mixtures ofwater with alcohols. For oral and rectal use, pharmaceutical forms suchas, for example, tablets, film-coated tablets, sugar-coated tablets,granules, hard and soft gelatin capsules, suppositories, solutions,including oily, alcoholic or aqueous solutions, syrups, juices or drops,furthermore suspensions or emulsions, can be used. For parenteral use,for example by injection or infusion, pharmaceutical forms such assolutions, for example aqueous solutions, can be used. For topical use,pharmaceutical forms such as ointments, creams, pastes, lotions, gels,sprays, foams, aerosols, solutions or powders can be used. Furthersuitable pharmaceutical forms are, for example, implants and patches andforms adapted to inhalation. The compounds of the formula I and theirphysiologically acceptable salts can also be lyophilized and theobtained lyophilizates used, for example, for the production ofinjectable compositions. In particular for topical application, alsoliposomal compositions are suitable. The pharmaceutical compositions andmedicaments can also contain one or more other active ingredientsand/or, for example, one or more vitamins.

As usual, the dosage of the compounds of the formula I depends on thecircumstances of the specific case and is adjusted by the physicianaccording to the customary rules and procedures. It depends, forexample, on the compound of the formula I administered and its potencyand duration of action, on the nature and severity of the individualsyndrome, on the sex, age, weight and the individual responsiveness ofthe human or animal to be treated, on whether the treatment is acute orchronic or prophylactic, or on whether further pharmaceutical activecompounds are administered in addition to a compound of the formula I.Normally, in the case of administration to an adult weighing about 75kg, a dose from about 0.1 mg to about 100 mg per kg per day, inparticular from about 1 mg to about 10 mg per kg per day (in each casein mg per kg of body weight), is sufficient. The daily dose can beadministered in the form of a single dose or divided into a number ofindividual doses, for example two, three or four individual doses. Theadministration can also be carried out continuously, for example bycontinuous injection or infusion. Depending on the individual behaviorin a specific case, it may be necessary to deviate upward or downwardfrom the indicated dosages.

Besides as a pharmaceutical active compound in human medicine andveterinary medicine, the compounds of the formula I can also be employedas an aid in biochemical investigations or as a scientific tool or fordiagnostic purposes, for example in in-vitro diagnoses of biologicalsamples, if an inhibition of the Edg-2 receptor is intended. Thecompounds of the formula I and their salts can also be used asintermediates for the preparation of further pharmaceutical activesubstances.

The following examples illustrate the invention.

ABBREVIATIONS

-   ACN acetonitrile-   DCM dichloromethane-   DIAD diisopropyl azodicarboxylate-   DIC 1,3-diisopropylcarbodiimide-   DMF dimethylformamide-   DMSO dimethyl sulfoxide-   EA ethyl acetate-   EDIA N-ethyldiisopropylamine-   EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   FMOC fluoren-9-ylmethoxycarbonyl-   HEP heptane-   HOBT 1-hydroxy-benzotriazole-   NMM N-methyl-morpholine-   TFA trifluoroacetic acid-   THF tetrahydrofuran

In general, reactions were carried out under argon. When examplecompounds containing a basic group were purified by preparative highpressure liquid chromatography (HPLC) on reversed phase (RP) columnmaterial and, as customary, the eluent was a gradient mixture of waterand acetonitrile containing trifluoroacetic acid, they were in partobtained in the form of their acid addition salts with trifluoroaceticacid, depending on the details of the workup such as evaporation orlyophilization conditions. In the names of the example compounds and thestructural formulae such contained trifluoroacetic acid is notspecified.

The prepared compounds were in general characterized by spectroscopicdata and chromatographic data, in particular mass spectra (MS) and HPLCretention times (Rt; in min) which were obtained by combined analyticalHPLC/MS characterization (LC/MS), and/or nuclear magnetic resonance(NMR) spectra. Unless specified otherwise, ¹H-NMR spectra were recordedat 500 MHz in D₆-DMSO as solvent at 298 K. In the NMR characterization,the chemical shift δ (in ppm), the number of hydrogen atoms (H) and themultiplicity (s: singlet, d: doublet, dd: double doublet, t: triplet,dt: double triplet, q: quartet, m: multiplet; br: broad) of the peaks asdetermined on printouts are given. In the MS characterization, ingeneral the mass number (m/z) of the peak of the molecular ion [M], e.g.[M⁺], or of a related ion such as the ion [M+1], e.g. [(M+1)⁺], i.e. theprotonated molecular ion [(M+H)⁺] abbreviated as [MH⁺], or the ion[M−1], e.g. [(M−1)⁻], i.e. the deprotonated molecular ion [(M−H)⁻],which was formed depending on the ionization method used, is given.Generally, the ionization method was electrospray ionization (ESI) oratmospheric pressure chemical ionization (APCI). The particulars of theLC/MS methods used are as follows.

Method LC1

Column: YMC J′ sphere H80, 20×2.1 mm, 4 μm; 30° C.; flow: 1.0 ml/min;eluent A: ACN; eluent B: water+0.05% TFA; gradient: from 4% A+96% B to95% A+5 B within 2.4 min, then to 4% A+96% B within 0.05 min, then 4%A+96% B for 0.05 min; MS ionization method: ESI⁺

Method LC2

Column: YMC J′ sphere H80, 20×2.1 mm, 4 μm; 30° C.; flow: 1.0 ml/min;eluent A: ACN; eluent B: water+0.05% TFA; gradient: from 4% A+96% B to95% A+5 B within 2.4 min, then to 4% A+96% B within 0.05 min, then 4%A+96% B for 0.05 min; MS ionization method: ESI⁺

Method LC3

Column: YMC J′ sphere H80, 33×2.1 mm, 4 μm; flow: 1.3 ml/min; eluent A:ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: from 5% A+95% B to95% A+5% B within 2.5 min, then 95% A+5% B for 0.5 min; then to 5% A+95%B within 0.2 min; MS ionization method: ESI⁺

Method LC4

Column: YMC J′ sphere H80, 33×2.1 mm, 4 μm; flow: 1.0 ml/min; eluent A:ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: from 5% A+95% B to95% A+5% B within 3.4 min, then 95% A+5% B for 1.0 min, then to 5% A+95%B within 0.2 min, then 5% A+95% B for 0.5 min; MS ionization method:ESI⁺

Method LC5

Column: YMC J′ sphere H80, 33×2.1 mm, 4 μm; flow: 1.3 ml/min; eluent A:ACN+0.08% formic acid; eluent B: water+0.1% formic acid; gradient: from5% A+95 B to 95% A+5% B within 2.5 min, then 95% A+5% B for 0.5 min; MSionization method: ESI⁺

Method LC6

Column: YMC J′ sphere H80, 33×2.1 mm, 4 μm; flow: 1.3 ml/min; eluent A:ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: from 5% A+95% B to95% A+5% B within 2.5 min, then to 5% A+95% B within 0.5 min; MSionization method: ESI⁺

Method LC7

Column: Thermo Javelin C18, 40×2.1 mm, 5 μm; flow: 1.0 ml/min; eluent A:ACN+0.1% TFA; eluent B: water+0.1% TFA; gradient: from 2% A+98% B to 80%A+20% B within 7.0 min, then to 100% A+0% B within 0.2 min, then 100%A+0% B for 1.0 min, then to 2% A+98% B within 0.3 min, then 2% A+98% Bfor 0.5 min; MS ionization method: ESI⁺

Method LC8

Column: Thermo Javelin C18, 40×2.1 mm, 5 μm; flow: 1.0 ml/min; eluent A:ACN+0.1% TFA; eluent B: water+0.1% TFA; gradient: from 2% A+98% B to 80%A+20% B within 5.0 min, then to 100% A+0% B within 0.2 min, then 100%A+0% B for 1.0 min, then to 2% A+98% B within 0.3 min, then 2% A+98% Bfor 0.5 min; MS ionization method: ESI⁺

Method LC9

Column: HP Waters Atlantis dC18, 50×2.1 mm, 5 μm; flow: 0.6 ml/min;eluent A: ACN+0.1% TFA; eluent B: water+0.1% TFA; gradient: from 2%A+98% B to 80% A+20% B within 5.0 min, then to 100% A+0% B within 0.2min, then 100% A+0% B for 1.0 min, then to 2% A+98% B within 0.3 min,then 2% A+98% B for 0.5 min; MS ionization method: ESI⁺

Method LC10

Column: YMC J′ sphere H80, 33×2.1 mm, 4 μm; flow: 1.3 ml/min; eluent A:ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: 5% A+95% B for 0.5min, then to 95% A+5% B within 3.0 min, then to 5% A+95% B within 0.5min; MS ionization method: ESI⁺

Method LC11

Column: YMC J′ sphere H80, 33×2.1 mm, 4 μm; flow: 1.3 ml/min; eluent A:ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: from 5% A+95% B to95% A+5% B within 2.5 min, then 95% A+5% B for 0.5 min; MS ionizationmethod: ESI⁺

Method LC12

Column: YMC J′ sphere H80, 33×2.1 mm, 4 μm; flow: 1 ml/min; eluent A:ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: 2% A+98% B for 1min, then to 95% A+5% B within 4 min, then 95% A+5% B for 1.25 min; MSionization method: ESI⁺

Method LC13

Column: YMC J′ sphere H80, 33×2.1 mm, 4 μm; flow: 1.3 ml/min; eluent A:ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: 5% A+95% B for 0.5min, then to 95% A+5% B within 3 min, then 95% A+5% B for 0.5 min; MSionization method: ESI⁺

Method LC14

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.3 ml/min, 50° C.;eluent A: ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: 5% A+95% Bfor 0.3 min, then to 95% A+5% B within 3.2 min, then 95% A+5% B for 0.5min; MS ionization method: ESI⁺

Method LC15

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.3 ml/min, 50° C.;eluent A: ACN+0.1% formic acid; eluent B: water+0.1% formic acid;gradient: from 3% A+97% B to 60% A+40% B within 3.5 min, then to 98%A+2% B within 0.5 min, then 98% A+2% B for 1 min, then to 3% A+97% Bwithin 0.2 min, then 3% A+97% B for 1.3 min; MS ionization method: APCI⁺

Method LC16

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.3 ml/min, eluentA: ACN+0.08% formic acid; eluent B: water+0.1% formic acid; gradient:from 3% A+97 B to 60% A+40% B within 3.5 min, then to 98% A+2% B within0.5 min, then 98% A+2% B for 1 min, then to 3% A+97% B within 0.2 min,then 3% A+97% B for 1.3 min; MS ionization method: ESI⁻

Method LC17

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.3 ml/min, eluentA: ACN+0.08% formic acid; eluent B: water+0.1% formic acid; gradient:from 3% A+97 B to 60% A+40% B within 3.5 min, then to 98% A+2% B within0.5 min, then 98% A+2% B for 1 min, then to 3% A+97% B within 0.2 min,then 3% A+97% B for 1.3 min; MS ionization method: ESI⁺

Method LC18

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.7 ml/min, 50° C.,eluent A: ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: 5% A+95% Bfor 0.2 min, then to 95% A+5% B within 2.2 min, then 95% A+5% B for 1.1min, then to 5% A+95% B within 0.1 min, then 5% A+95% B for 0.9 min; MSionization method: ESI⁺

Method LC19

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.3 ml/min, 50° C.,eluent A: ACN+0.1% formic acid; eluent B: water+0.1% formic acid;gradient: from 3% A+97% B to 60% A+40% B within 3.5 min, then to 98%A+2% B within 0.5 min, then 98% A+2% B for 1 min, then to 3% A+97% Bwithin 0.2 min, then 3% A+97% B for 1.3 min; MS ionization method: ESI⁺

Method LC20

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.3 ml/min, eluentA: ACN+0.08% formic acid; eluent B: water+0.1% formic acid; gradient:from 3% A+97% B to 98% A+2% B within 18 min, then 98% A+2% B for 1 min,then to 3% A+97% B within 0.5 min, then 3% A+97% B for 0.5 min; MSionization method: ESI⁺

Method LC21

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.3 ml/min, 50° C.,eluent A: ACN+0.1% formic acid; eluent B: water+0.1% formic acid;gradient: from 3% A+97% B to 60% A+40% B within 3.5 min, then to 98%A+2% B within 0.5 min, then 98% A+2% B for 1 min, then to 3% A+97% Bwithin 0.2 min, then 3% A+97% B for 1.3 min; MS ionization method: ESI⁻

Method LC22

Column: YMC J′ sphere H80, 33×2.1 mm, 4 μm; flow: 1 ml/min; eluent A:ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: from 5% A+95% B to95% A+5% B within 3.7 min; MS ionization method: ESI⁺

EXAMPLE 12-[4-Bromo-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acidmethyl ester

Step 1 4-Bromo-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester

4-Bromo-3-hydroxy-benzoic acid methyl ester (1.00 g, 4.32 mmol) andtriphenylphosphine (1.36 g, 5.19 mmol) were dissolved in THF.2-(3-Methylphenyl)-ethanol (2-m-tolyl-ethanol) (0.707 g, 5.19 mmol) wasadded, the mixture was cooled in an ice bath, and DIAD (1.05 g, 5.19mmol) was added slowly with stirring. The ice bath was removed andstirring continued overnight at room temperature. The volatiles wereevaporated in vacuo, and the residue was purified by silica gelchromatography (HEP/EA gradient) to give 1.55 g of the title compound.

Step 2 4-Bromo-3-(2-m-tolyl-ethoxy)-benzoic acid

The compound of step 1 (0.50 g, 1.43 mmol) was dissolved in dioxane (5ml), lithium hydroxide (7.1 ml of an aqueous 1 M (i.e. 1 mol per liter)solution) was added, and the mixture was reacted overnight. The mixturewas partitioned between 2 N hydrochloric acid and EA, the aqueous phaseextracted with EA, and the organic extracts were dried over sodiumsulfate, filtered and evaporated to dryness in vacuo to give 0.414 g ofthe title compound.

¹H-NMR: δ=13.2 (br s, 1H); 7.7 (d, 1H); 7.52 (d, 1H); 7.42 (dd, 1H);7.22-7.11 (m, 3H); 7.02 (d, 1H); 4.30 (t, 2H); 3.03 (t, 2H); 2.29 (s,3H)

Step 3 2-[4-Bromo-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid methyl ester

The compound of step 2 (0.410 g, 1.22 mmol) was dissolved in DMF (5 ml),EDIA (0.790 g, 6.12 mmol), HOBT (33 mg, 0.244 mmol), and2-amino-indane-2-carboxylic acid methyl ester hydrochloride (0.246 g,1.47 mmol) were added, the mixture was cooled in an ice bath and EDC(352 mg, 1.84 mmol) was added. The mixture was stirred overnight. Thevolatiles were evaporated in vacuo, the mixture was partitioned between2 N hydrochloric acid and EA, the organic phase was dried over magnesiumsulfate and evaporated to dryness. The residue was purified by silicagel chromatography (HEP/EA gradient) to give 0.56 g of the titlecompound.

LC/MS (Method LC1): Rt=1.98 min; m/z=508.1/510.1 [MH⁺]

EXAMPLE 22-[4-Bromo-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid

The compound of example 1 (60 mg, 0.118 mmol) was dissolved in dioxane(1.5 ml), lithium hydroxide (0.59 ml of an aqueous 1 M solution) wasadded and the mixture was reacted for 20 min at 60° C. The mixture waspartitioned between 2 N hydrochloric acid and EA, the aqueous phaseextracted with EA, and the organic extracts were dried over sodiumsulfate, filtered and evaporated to dryness in vacuo. The residue wasstirred overnight with a mixture of diethyl ether and HEP, filtered, andthe solid was dried in vacuo to give 43 mg of the title compound.

¹H-NMR: δ=12.45 (br s, 1H); 8.87 (s, 1H); 7.64 (d, 1H); 7.46 (d, 1H);7.37 (dd, 1H); 7.25-7.11 (m, 7H); 7.02 (d, 1H); 4.27 (t, 2H); 3.60 (d,2H); 3.37 (d, 2H); 3.02 (t, 2H); 2.28 (s, 3H)

EXAMPLE 32-[4-Methylsulfanyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid methyl ester

Step 1 4-Nitro-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester

3-Hydroxy-4-nitro-benzoic acid methyl ester (1.00 g, 5.07 mmol) and2-(3-methylphenyl)-ethanol (0.829 g, 6.09 mmol) were reacted in analogyto step 1 of example 1 to give 1.39 g of the title compound.

¹H-NMR: δ=7.96 (d, 1H); 7.75 (s, 1H); 7.63 (d, 1H); 7.18 (t, 1H); 7.11(s, 1H); 7.08 (d, 1H); 7.03 (d, 1H); 4.41 (t, 2H); 3.89 (s, 3H); 3.01(t, 2H); 2.28 (s, 3H)

Step 2 4-Methylsulfanyl-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester

The compound of step 1 (900 mg, 2.85 mmol) was dissolved in1,3-dimethyl-2-imidazolidinone (6 ml), and sodium methanethiolate (0.23g, 3.29 mmol) was added. The mixture was reacted at room temperature for60 h, then partitioned between a saturated sodium chloride solution andEA, and the aqueous phase extracted with EA. The organic extracts weredried over sodium sulfate, filtered and evaporated to dryness. Theresidue was purified by silica gel chromatography (HEP/EA gradient) togive 600 mg of the title compound.

¹H-NMR: δ=7.56 (d, 1H); 7.39 (s, 1H); 7.23 (d, 1H); 7.21-7.12 (m, 3H);7.02 (d, 1H); 4.25 (t, 2H); 3.82 (s, 3H); 3.01 (t, 2H); 2.41 (s, 3H);2.29 (s, 3H)

Step 3 4-Methylsulfanyl-3-(2-m-tolyl-ethoxy)-benzoic acid

The compound of step 2 (450 mg, 1.42 mmol) was hydrolyzed in analogy toexample 2 to give 395 mg of the title compound.

¹H-NMR: δ=12.8 (br s, 1H); 7.55 (d, 1H); 7.38 (s, 1H); 7.23-7.10 (m,4H); 7.02 (d, 1H); 4.25 (t, 2H); 3.82 (s, 3H); 3.00 (t, 2H); 2.41 (s,3H); 2.29 (s, 3H)

Step 42-[4-Methylsulfanyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid methyl ester

The compound of step 3 (395 mg, 1.31 mmol) was dissolved in DCM (5 ml).DMF (29 mg, 0.39 mmol) and oxalyl chloride (3.9 ml of a 2 M solution inDCM) were added at room temperature. The mixture was stirred for 60 min,evaporated to dryness in vacuo, dissolved in dioxane and evaporatedagain. The residue was dissolved in DCM (2 ml) and the solution wasslowly added with stirring to an ice-cooled mixture of2-amino-indane-2-carboxylic acid methyl ester hydrochloride (5.42 g,23.8 mmol), EA and an excess of saturated aqueous sodiumhydrogencarbonate solution. After 2 h, the organic layer was separated,washed with a saturated sodium chloride solution, dried over sodiumsulfate, filtered and evaporated to dryness. 582 mg of the titlecompound were obtained.

¹H-NMR: δ=8.86 (s, 1H); 7.5 (dd, 1H); 7.36 (d, 1H); 7.25-7.11 (m, 8H);7.02 (d, 1H); 4.23 (t, 2H); 3.61 (d, 2H); 3.60 (s, 3H); 3.37 (d, 2H);3.01 (t, 2H); 2.39 (s, 3H); 2.28 (s, 3H)

EXAMPLE 42-[4-Methylsulfanyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The compound of example 3 (580 mg, 1.22 mmol) was hydrolyzed in analogyto example 2 to give 480 mg of the title compound.

¹H-NMR: δ=12.4 (br s, 1H); 8.73 (s, 1H); 7.50 (dd, 1H); 7.35 (d, 1H);7.24-7.11 (m, 8H); 7.02 (d, 1H); 4.24 (t, 2H); 3.59 (d, 2H); 3.37 (d,2H); 3.01 (t, 2H); 2.39 (s, 3H); 2.28 (s, 3H)

EXAMPLE 52-[4-Methanesulfinyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The compound of example 4 (100 mg, 0.216 mmol) was dissolved in aceticacid (7.5 ml), hydrogen peroxide (74 mg of a 30% solution in water, 0.65mmol) was added, and the mixture was reacted at room temperature for 9h. The mixture was partitioned between EA and a 1% aqueous sodiumsulfite solution, the aqueous phase extracted with EA, and the organicextracts were dried over sodium sulfate, filtered and evaporated todryness. The residue was stirred with diethyl ether, filtered, and driedin vacuo to give 79 mg of the title compound.

LC/MS (Method LC1): Rt=1.48 min; m/z=478.2 [MH⁺]

EXAMPLE 62-[4-Methanesulfonyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The compound of example 4 (140 mg, 0.30 mmol) was dissolved in aceticacid (7.5 ml), hydrogen peroxide (103 mg of a 30% solution in water,0.91 mmol) was added and the mixture was reacted at 70° C. for 8 h. Themixture was partitioned between EA and 1% aqueous sodium sulfitesolution, the aqueous phase extracted with EA, and the organic extractswere dried over sodium sulfate, filtered and evaporated to dryness. Theresidue was stirred with diethyl ether, filtered, and dried in vacuo togive 143 mg of the title compound.

LC/MS (Method LC1): Rt=1.55 min; m/z=494.0 [MH⁺]

EXAMPLE 72-[4-Acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acidmethyl ester

4-Acetyl-3-hydroxy-benzoic acid (M. E. Zwaagstra et. al., J. Med. Chem.40 (1997), 1075-1089) was reacted with 2-amino-indane-2-carboxylic acidmethyl ester hydrochloride in analogy to step 3 of example 1. From theobtained 2-[4-acetyl-3-hydroxy-benzoylamino]-indane-2-carboxylic acidmethyl ester, the title compound was obtained by reaction with2-(3-methylphenyl)-ethanol in analogy to step 1 of example 1.

LC/MS (Method LC1): Rt=1.83 min; m/z=472.2 [MH⁺]

EXAMPLE 82-[4-Acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid

From the compound of example 7, the title compound was obtained byhydrolysis with lithium hydroxide in analogy to example 2.

LC/MS (Method LC1): Rt=1.67 min; m/z=458.0 [MH⁺]

EXAMPLE 92-[4-(1-Hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The compound of example 7 (300 mg, 0.636 mmol) was dissolved in 3 ml ofethanol, the mixture was cooled in an ice bath and sodium borohydride(24.1 mg, 0.636 mmol) was added. The reaction mixture was allowed towarm to room temperature and stirring was continued for 4 h. The mixturewas partitioned between EA and a saturated aqueous sodiumhydrogencarbonate solution, the aqueous phase extracted with EA, and theorganic extracts were dried over sodium sulfate, filtered and evaporatedto dryness. The residue was purified by preparative RP HPLC (water/ACNgradient) to give a mixture of2-[4-(1-hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid methyl ester and2-[4-(1-hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid ethyl ester.

LC/MS (Method LC1): Rt=1.70 min; m/z=474.2 [MH⁺](2-[4-(1-hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid methyl ester)

LC/MS (Method LC1): Rt=1.76 min; m/z=488.2 [MH⁺](2-[4-(1-hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid ethyl ester)

From the mixture of the methyl ester and the ethyl ester, the titlecompound was obtained by hydrolysis with lithium hydroxide in analogy toexample 2.

LC/MS (Method LC1): Rt=1.54 min; m/z=460.2 [MH⁺]

EXAMPLE 102-[4-Ethyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid

The compound of example 9 (80 mg, 0.174 mmol) was dissolved in methanoland hydrogenated in an H-cube™ hydrogenation reactor (ThalesNano,Budapest, Hungary) at a hydrogen pressure of 100 bar over a 10%palladium on charcoal cartridge. The reaction mixture was evaporated todryness and the residue purified by preparative RP HPLC (water/ACNgradient).

¹H-NMR: δ=12.3 (br s, 1H); 8.72 (s, 1H); 7.40-7.33 (m, 2H); 7.25-7.12(m, 7H); 7.10 (d, 1H); 7.02 (d, 1H); 4.20 (t, 2H); 3.59 (d, 2H); 3.37(d, 2H); 3.02 (t, 2H); 2.56-2.51 (m, 2H); 2.27 (s, 3H); 1.02 (t, 3H)

EXAMPLE 112-[4-(1-Fluoro-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The mixture of2-[4-(1-hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid methyl ester and2-[4-(1-hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid ethyl ester obtained in example 9 (50 mg) was dissolved in DCM, anddiethylaminosulfur trifluoride (33 mg, 0.204 mmol) was added in twoportions (second portion after 3.5 h). After complete conversion asdetected by HPLC, the mixture was partitioned between EA and a saturatedaqueous sodium hydrogencarbonate solution and the aqueous phaseextracted with EA. The combined organic extracts were dried over sodiumsulfate, filtered and evaporated to dryness. The residue was stirredwith a HEP/diethyl ether mixture, filtered, and dried in vacuo. Theobtained ester was hydrolyzed in analogy to example 2 to give 12 mg ofthe title compound.

¹H-NMR: δ=12.4 (br s, 1H); 8.82 (s, 1H); 7.49 (d, 1H); 7.41 (s, 1H);7.37 (d, 1H); 7.25-7.12 (m, 6H); 7.10 (d, 1H); 7.03 (d, 1H); 5.83/5.74(dq, 1H); 4.26 (t, 2H); 3.58 (d, 2H); 3.39 (d, 2H); 3.02 (d, 2H); 2.27(s, 3H); 1.40/1.35 (dd, 3H)

EXAMPLE 122-[4-Ethoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid

Step 1 4-Ethoxy-3-hydroxy-benzoic acid ethyl ester

3,4-Dihydroxybenzoic acid ethyl ester (3.00 g, 16.0 mmol) was suspendedin DMF (10 ml), potassium carbonate (2.21 g, 16.0 mmol) was added, themixture was stirred for 5 min at room temperature, and then iodoethane(2.49 g, 16.0 mmol) was added. The mixture was stirred overnight, theaddition of potassium carbonate and of iodoethane was repeated, and themixture was stirred overnight again. The mixture was partitioned between2 N hydrochloric acid and EA, the aqueous phase extracted with EA, andthe combined organic extracts were washed with a saturated sodiumhydrogencarbonate solution and a saturated sodium chloride solution,dried over sodium sulfate, filtered, and evaporated to dryness. Theresidue was purified by silica gel chromatography (HEP/EA gradient).

LC/MS (Method LC1): Rt=1.28 min; m/z=211.1 [MH⁺]

Step 22-[4-Ethoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid

From the compound of step 1, the title compound was obtained by reactionwith 2-(3-methylphenyl)-ethanol in analogy to step 1 of example 1,hydrolysis of the ester group in analogy to example 2, reaction of theobtained carboxylic acid with 2-amino-indane-2-carboxylic acid methylester hydrochloride in analogy to step 1 of example 15, and hydrolysisof the ester group in analogy to example 2.

¹H-NMR: δ=12.4 (br s, 1H); 8.64 (s, 1H); 7.46 (d, 1H); 7.41 (s, 1H);7.22-7.10 (m, 7H); 7.02 (d, 1H); 6.99 (d, 1H); 4.16 (t, 2H); 4.04 (q,2H); 3.53 (d, 2H); 3.3-3.4 (2H); 2.98 (t, 2H); 2.28 (s, 3H); 1.32 (t,3H)

EXAMPLE 132-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acidmethyl ester

Step 1 4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid

From 3-hydroxy-4-methoxy-benzoic acid methyl ester, the title compoundwas obtained by reaction with 2-(3-methylphenyl)-ethanol in analogy tostep 1 of example 1 and hydrolysis of the ester group in analogy toexample 2.

¹H-NMR: δ=12.65 (br s, 1H); 7.56 (dd, 1H); 7.44 (d, 1H); 7.19 (t, 1H);7.17-7.15 (m, 1H); 7.12 (d, 1H); 7.06-7.02 (m, 2H); 4.19 (t, 2H); 3.83(s, 3H); 3.01 (t, 2H); 2.29 (s, 3H)

Step 22-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acidmethyl ester

The compound of step 1 (1.98 g, 6.91 mmol) was dissolved in thionylchloride (10 ml) and stirred for 20 min at 60° C. The solution wasevaporated to dryness in vacuo and the residue was evaporated twice withdioxane in vacuo. The residue was dissolved in a little DCM and added toa well-stirred mixture of 2-amino-indane-2-carboxylic acid methyl esterhydrochloride (1.50 g, 6.58 mmol) in EA and an excess of a saturatedaqueous sodium hydrogencarbonate solution. The mixture was stirred for30 min at room temperature. The layers were separated, the aqueous phasewas extracted with EA, the combined organic phases were washed withbrine, dried over sodium sulfate, filtered and evaporated to dryness.This residue was stirred with diethyl ether overnight, filtered anddried in vacuo to give 1.92 g of the title compound.

¹H-NMR: δ=8.78 (s, 1H); 7.50 (dd, 1H); 7.43 (d, 1H); 7.24-7.14 (m, 6H);7.11 (d, 1H); 7.03 (d, 1H); 7.01 (d, 1H); 4.17 (t, 2H); 3.80 (s, 3H);3.59 (d, 2H); 3.59 (s, 3H); 3.36 (d, 2H); 3.00 (t, 2H); 2.28 (s, 3H)

EXAMPLE 142-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid

The compound of example 13 (1.92 g, 4.18 mmol) was dissolved in dioxane(40 ml), lithium hydroxide (10 ml, 1 M solution in water) was added andthe mixture was stirred for 30 min at 60° C. The mixture was partitionedbetween 2 N hydrochloric acid and EA, the aqueous phase extracted withEA, and the combined organic extracts were washed with brine, dried oversodium sulfate, filtered and evaporated to dryness. The residue wasstirred overnight in EA, filtered, and the crystals were dried in vacuoto give 1.35 g of the title compound.

¹H-NMR: δ=12.36 (br s, 1H); 8.63 (s, 1H); 7.50 (dd, 1H); 7.43 (d, 1H);7.23-7.13 (m, 6H); 7.11 (d, 1H); 7.03 (d, 1H); 7.00 (d, 1H); 4.17 (t,2H); 3.79 (s, 3H); 3.58 (d, 2H); 3.37 (d, 2H); 3.00 (t, 2H); 2.28 (s,3H)

EXAMPLE 152-{4-Methoxy-3-[2-(3-methylsulfanyl-phenyl)-ethoxy]-benzoylamino}-indane-2-carboxylicacid methyl ester

Step 1 2-(3-Acetoxy-4-methoxy-benzoylamino)-indane-2-carboxylic acidmethyl ester

3-Acetoxy-4-methoxy-benzoic acid (5.00 g, 23.8 mmol) was dissolved inDCM (50 ml). DMF (167 mg, 2.38 mmol) and oxalyl chloride (35.6 ml of a 2M solution in DCM) were added at room temperature. The mixture wasstirred for 20 min, evaporated to dryness in vacuo, the residueredissolved in DCM and evaporated again. The residue was dissolved inDCM and slowly added to a stirred mixture of 2-amino-indane-2-carboxylicacid methyl ester hydrochloride (5.42 g, 23.8 mmol), EA and an excess ofa saturated aqueous sodium hydrogencarbonate solution. After 90 min theorganic layer was separated and washed with a saturated sodiumhydrogencarbonate solution, 2 M hydrochloric acid and a saturated sodiumchloride solution, dried over sodium sulfate, filtered and evaporated todryness to give 8.95 g of the title compound.

¹H-NMR: δ=8.88 (s, 1H); 7.80 (dd, 1H); 7.62 (d, 1H); 7.28-7.13 (m, 5H);3.81 (s, 3H); 3.60 (s, 3H); 3.58 (d, 2H); 3.37 (d, 2H); 2.27 (s, 3H)

Step 2 2-(3-Hydroxy-4-methoxy-benzoylamino)-indane-2-carboxylic acidmethyl ester

The compound of step 1 (3.44 g, 8.97 mmol) was dissolved in methanol (50ml), potassium carbonate (248 mg, 1.79 mmol) was added and the mixturewas stirred for 2 h at room temperature. The mixture was evaporated todryness, the residue partitioned between EA and 1 N hydrochloric acidand the aqueous phase extracted with EA. The combined organic extractswere dried over magnesium sulfate, filtered and evaporated to dryness togive 2.80 g of the title compound.

¹H-NMR: δ=9.14 (s, 1H); 8.71 (s, 1H); 7.32 (dd, 1H); 7.29 (d, 1H);7.24-7.20 (m, 2H); 7.19-7.13 (m, 2H); 6.93 (d, 2H); 3.80 (s, 3H); 3.60(s, 3H); 3.56 (d, 2H); 3.38 (d, 2H)

Step 32-{4-Methoxy-3-[2-(3-methylsulfanyl-phenyl)-ethoxy]-benzoylamino}-indane-2-carboxylicacid methyl ester

The compound of step 2 (0.380 g, 1.11 mmol) and triphenylphosphine(0.461 g, 1.67 mmol) were dissolved in THF.2-(3-Methylsulfanyl-phenyl)-ethanol (0.281 g, 1.67 mmol) and DIAD (0.359g, 1.67 mmol) were added and the reaction mixture was stirred at roomtemperature for 2 h. The volatiles were evaporated in vacuo and theresidue was purified by preparative RP HPLC (water/ACN gradient) to give0.217 g of the title compound.

¹H-NMR: δ=8.78 (s, 1H); 7.50 (d, 1H); 7.41 (s, 1H); 7.28-7.20 (m, 4H);7.20-7.13 (m, 2H); 7.13-7.08 (m, 2H); 7.00 (d, 1H); 4.18 (t, 2H); 3.79(s, 3H); 3.62-3.55 (m, 5H); 3.38 (d, 2H); 3.01 (t, 2H); 2.45 (s, 3H)

EXAMPLE 162-{4-Methoxy-3-[2-(3-methylsulfanyl-phenyl)-ethoxy]-benzoylamino}-indane-2-carboxylicacid

The compound of example 15 (195 mg, 0.397 mmol) was dissolved in dioxane(2 ml), lithium hydroxide (1.99 ml of an aqueous 1 M solution, 1.99mmol) was added, and the mixture was stirred at 60° C. for 1 h. Themixture was partitioned between 2 N hydrochloric acid and EA, theaqueous phase extracted with EA, and the combined organic extracts weredried over sodium sulfate, filtered and evaporated to dryness to give180 mg of the title compound.

¹H-NMR: δ=12.37 (br s, 1H); 8.65 (s, 1H); 7.47 (d, 1H); 7.41 (s, 1H);7.29-7.18 (m, 4H); 7.18-7.08 (m, 4H); 7.01 (d, 1H); 4.17 (t, 2H); 3.79(s, 3H); 3.54 (d, 2H); 3.37 (d, 2H); 3.01 (t, 2H); 2.45 (s, 3H)

EXAMPLE 172-{3-[2-(3-Methanesulfinyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

The compound of example 16 (35 mg, 0.078 mmol) was dissolved in aceticacid (2.5 ml), hydrogen peroxide (43 mg of a 30% solution in water, 0.38mmol) was added and the mixture was stirred at room temperature for 2 h.The mixture was partitioned between EA and a 1% aqueous sodium sulfitesolution, the aqueous phase extracted with EA, and the combined organicextracts were dried over sodium sulfate, filtered and evaporated todryness to give 36 mg of the title compound.

¹H-NMR: δ=12.3 (br s, 1H); 8.62 (s, 1H); 7.65 (s, 1H); 7.56-7.47 (m,4H); 7.43 (d, 1H); 7.23-7.19 (m, 2H); 7.17-7.12 (m, 2H); 7.00 (d, 1H);4.24 (t, 2H); 3.80 (s, 3H); 3.57 (d, 2H); 3.38 (d, 2H); 3.14 (t, 2H);2.72 (s, 3H)

EXAMPLE 182-{3-[2-(3-Methanesulfonyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

The title compound was synthesized in analogy to example 17 except thatthe reaction temperature was 70° C. Yield: 36 mg.

¹H-NMR: δ=12.35 (br s, 1H); 8.64 (s, 1H); 7.92 (s, 1H); 7.78 (d, 1H);7.70 (d, 1H); 7.58 (dd, 1H); 7.49 (dd, 1H); 7.42 (d, 1H); 7.22-7.19 (m,2H); 7.18-7.12 (m, 2H); 7.00 (d, 1H); 4.24 (t, 2H); 3.79 (s, 3H); 3.56(d, 2H); 3.37 (d, 2H); 3.19 (s, 3H); 3.18 (t, 2H)

In analogy to the above examples, the example compounds of the formulaIm listed in table 1 were prepared. In the formulae of the groups R⁹⁰ intable 1 the line crossed with the symbol

represents the free bond via which the group R⁹⁰ is bonded to the oxygenatom which is attached to the 3-position of the benzoyl group depictedin formula Im. I.e., in the formula of the complete molecule theterminal endpoint of the line crossed with the said symbol ends at theoxygen atom attached to the 3-position of the benzoyl group. Thecompounds can be named as2-[3-(R⁹⁰-oxy)-4-methoxy-benzoylamino]-indane-2-carboxylic acid, forexample as2-{3-[2-(3-cyclopropyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid in the case of example 21.

TABLE 1 Example compounds of the formula Im       Example

    LC/MS Method     m/z [MH⁺]     Retention time [min] 19

LC3 532.09 2.04 20

LC1 464.20 1.62 21

LC1 472.2 1.68 22

LC1 460.2 1.70 23

LC1 460.2 1.65 24

LC1 472.2 1.70 25

LC1 474.2 1.75 26

LC2 457.1 1.48 27

LC1 476.2 1.35 28

LC3 430.3 1.41 29

LC3 462.35 1.82 30

LC3 438.36 2.04 31

LC3 419.28 1.15 32

LC4 471.27 2.14 33

LC3 386.28 1.41 34

LC3 460.38 1.96 35

LC3 384.31 1.73 36

LC3 398.36 1.81 37

LC4 398.25 2.29 38

LC3 412.31 1.45 39

LC3 452.30 1.86 40

LC3 474.39 2.06 41

LC3 446.34 1.93 42

LC3 410.34 1.85 43

LC3 412.33 1.92 44

LC3 482.36 1.97 45

LC3 444.33 1.86 46

LC3 476.33 1.80 47

LC3 500.31 1.94 48

LC4 439.29 1.22 49

LC3 441.35 1.18 50

LC3 422.33 1.87 51

LC3 520.35 1.48 52

LC3 483.26 1.60 53

LC3 515.37 1.81 54

LC4 533.25 2.37 55

LC4 449.26 1.24 56

LC4 456.27 2.09 57

LC3 438.36 2.06 58

LC3 477.26 1.28 59

LC3 426.35 2.03 60

LC3 490.37 1.94 61

LC3 452.38 2.16 62

LC3 480.31 2.00 63

LC3 461.32 1.25 64

LC3 439.33 1.16 65

LC3 446.33 1.91 66

LC4 529.34 1.49 67

LC3 512.38 1.23 68

LC3 453.34 1.38 69

LC3 472.22 1.27 70

LC3 513.35 1.85 71

LC4 436.26 1.42 72

LC3 474.30 1.89 73

LC3 484.33 1.24 74

LC3 506.28 1.64 75

LC4 468.24 1.32 76

LC3 488.23 1.25 77

LC3 504.23 1.22 78

LC3 454.22 1.49 79

LC3 485.19 1.64 80

LC3 436.23 1.44 81

LC3 476.26 2.19 82

LC3 396.20 1.72 83

LC3 501.24 1.33 84

LC3 442.21 1.49 85

LC3 453.23 1.19 86

LC3 396.20 1.75 87

LC3 434.22 1.89 88

LC3 437.2 1.55 89

LC3 502.18 1.82 90

LC3 488.21 1.46 91

LC3 516.31 1.26

EXAMPLE 92 Starting Compound (1-m-Tolyl-cyclopropyl)-methanol

m-Tolylacetonitrile (1.00 g, 7.62 mmol) and 1,2-dibromoethane (1.86 g,9.91 mmol) were dissolved in DMF (5 ml). The mixture was cooled in anice bath and potassium tert-butoxide (855 mg, 19.1 mmol) was addedslowly with stirring. After stirring for 30 min, the mixture waspartitioned between EA and water. The organic layer was washed withwater, dried over sodium chloride, decanted and evaporated to dryness.

After silica gel chromatography of the residue (HEP/EA gradient), anapproximately 1:1 mixture of 1-m-tolyl-cyclopropanecarbonitrile and thestarting compound m-tolylacetonitrile was obtained.

The obtained mixture of nitriles (500 mg) was dissolved in ethanol (2ml) and 50 aqueous potassium hydroxide (2 ml). The mixture was reactedwith microwave-heating at 140° C. for 4 h in a tightly closed vial. Thenthe mixture was partitioned between EA and 2 N hydrochloric acid, theaqueous phase extracted with EA, and the combined organic extracts driedover sodium chloride, decanted and evaporated to dryness to give amixture of 1-m-tolyl-cyclopropanecarboxylic acid amide andm-tolyl-acetamide.

The obtained mixture of amides (600 mg) was dissolved in acetic acid(8.5 ml) and acetic anhydride (14.5 ml), the mixture was cooled in anice bath, sodium nitrite (1.97 g, 28.5 mmol) was added, and the mixturewas stirred for 2 h at room temperature. Water (15 ml) was added and themixture was heated to 60° C. for 30 min. After evaporation to dryness invacuo, the residue was partitioned between EA and 2 N hydrochloric acid,the aqueous phase extracted with EA, and the combined organic extractswere dried over sodium sulfate, decanted and evaporated to dryness toyield an approximately 1:1 mixture of 1-m-tolyl-cyclopropanecarboxylicacid and m-tolyl-acetic acid.

The obtained mixture of acids (430 mg) was dissolved in dimethoxyethane(8 ml), NMM (272 mg, 2.68 mmol) and isobutyl chloroformate (367 mg, 2.68mmol) were added with stirring. After a few minutes, the mixture wasfiltered and sodium borohydride (369 mg, 9.76 mmol) was added to theclear filtrate. After cautious addition of water (4 ml; violentformation of hydrogen) stirring was continued for a few minutes untilthe reaction ceased, the mixture was partitioned between EA and 2 Nhydrochloric acid, the aqueous phase extracted with EA, and the combinedorganic extracts were dried over sodium sulfate, decanted and evaporatedto dryness. This residue was purified by preparative RP HPLC (water/ACNgradient) to give 133 mg of the title compound.

¹H-NMR: δ=7.18-7.06 (m, 3H); 6.98 (d, 1H); 4.59 (t, 1H); 3.51 (d, 2H);0.83-0.78 (m, 2H); 0.70-0.67 (m, 2H)

EXAMPLE 93 Starting Compound 2-(2-Fluoro-5-methyl-phenyl)-ethanol

In analogy to the procedure described in M. Jorgensen et al., J. Am.Chem. Soc. 124 (2002), 12557-12565, in a first flask, dicyclohexylamine(3.06 g, 16.9 mmol) was dissolved in toluene and cooled in an ice bath.n-Butyllithium (6.14 ml, 2.5 M solution in hexane) was added. After 5min, tert-butyl acetate (1.78 g, 15.3 mmol) was added slowly. A secondflask was charged with tri-(tert-butyl)phosphonium tetrafluoroborate (83mg, 0.30 mmol) and tris(dibenzylideneacetone)dipalladium(0) (146 mg,0.153 mmol) and thoroughly flushed with argon. Toluene (100 ml) wasadded, followed by 3-bromo-4-fluoro-toluene (2.90 g, 15.3 mmol) and bythe contents of the first flask. After stirring overnight, the formedsuspension was filtered over a small plug of silica gel which was washedrepeatedly with diethyl ether. The filtrates were evaporated in vacuoand the residue was purified by silica gel chromatography (HEP/EAgradient) to give 2.81 g of (2-fluoro-5-methyl-phenyl)-acetic acidtert-butyl ester.

¹H-NMR: δ=7.12-7.07 (m, 2H); 7.03 (t, 1H); 3.54 (s, 2H); 2.25 (s, 3H);1.39 (s, 9H)

A flask was charged with lithium aluminium hydride (0.846 g, 22.3 mmol)and flushed with argon. THF (8 ml) was added, and the obtained(2-fluoro-5-methyl-phenyl)-acetic acid tert-butyl ester was slowly addedwith stirring. The reaction took place immediately. After 2 min, diethylether (30 ml) and EA (2.5 ml) were added. Then water was addedcautiously and slowly with stirring until a greyish precipitate formed.

The solution was decanted and the precipitate was washed with EA. Thecombined solutions were dried over sodium sulfate, filtered andevaporated to dryness. The residue was purified by silica gelchromatography (HEP/EA gradient) to give 0.55 g of the title compound.

¹H-NMR: δ=7.10 (d, 1H); 7.05-6.96 (m, 2H); 4.70 (t, 1H); 3.56 (dt, 2H);2.71 (t, 2H); 2.25 (s, 3H)

EXAMPLE 942-{3-[2-(3-Cyano-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

Step 1 3-[2-(3-Bromo-phenyl)-ethoxy]-4-methoxy-benzoic acid methyl ester

Methyl 3-hydroxy-4-methoxybenzoate (500 mg, 2.75 mmol) andtriphenylphosphine (1.08 g, 4.12 mmol) were dissolved in THF (13 ml),the solution was cooled in an ice bath and 2-(3-bromophenyl)-ethanol(662 mg, 3.29 mmol) and DIAD (886 mg, 4.12 mmol) were addedsequentially. Stirring was continued for 3 h at room temperature. Thereaction mixture was evaporated to dryness and the residue purified bypreparative RP HPLC (water/ACN gradient) to give 900 mg of the titlecompound.

¹H-NMR: δ=7.62-7.58 (m, 2H); 7.45 (d, 1H); 7.41 (d, 1H); 7.35 (d, 1H);7.28 (dd, 1H); 7.08 (d, 1H); 4.22 (t, 2H); 3.83 (s, 3H); 3.80 (s, 3H);3.01 (t, 2H)

Step 2 3-[2-(3-Cyano-phenyl)-ethoxy]-4-methoxy-benzoic acid methyl ester

A flask was charged with zinc cyanide (129 mg, 1.10 mmol) andtetrakis(triphenylphosphine)palladium(0) (63 mg, 0.0547 mmol). Under anatmosphere of argon, a solution of the compound of step 1 (400 mg, 1.10mmol) in DMF (1.9 ml) was added to the mixture. After stirring at 150°C. for 1 h and cooling, the mixture was diluted with methyl tert-butylether and filtered over celite. The filtrate was washed with water,dried over magnesium sulfate, filtered and evaporated to dryness to give275 mg of the title compound.

¹H-NMR: δ=7.85 (s, 1H); 7.70 (dd, 1H); 7.58 (dd, 1H); 7.51 (dd, 1H);7.44 (d, 1H); 7.07 (d, 1H); 4.26 (t, 2H); 3.82 (s, 3H); 3.80 (s, 3H);3.11 (t, 2H)

Step 3 3-[2-(3-Cyano-phenyl)-ethoxy]-4-methoxy-benzoic acid

The compound of step 2 (274 mg, 0.883 mmol) was dissolved in dioxane(4.5 ml), lithium hydroxide (4.42 ml of a 1 M aqueous solution, 4.42mmol) was added, and the mixture was stirred at 60° C. for 30 min. Themixture was partitioned between 2 N hydrochloric acid and EA, theaqueous phase extracted with EA, and the combined organic extracts weredried over sodium sulfate, filtered and evaporated to dryness. Theresidue was purified by preparative RP HPLC (water/ACN gradient) to give160 mg of the title compound.

¹H-NMR: δ=12.65 (br s, 1H); 7.83 (s, 1H); 7.73-7.68 (m, 2H); 7.60-7.50(m, 2H); 7.45 (d, 1H); 7.04 (d, 1H); 4.25 (t, 2H); 3.81 (s, 3H); 3.11(t, 2H)

Step 42-{3-[2-(3-Cyano-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid methyl ester

From the compound of step 3 and 2-amino-indane-2-carboxylic acid methylester hydrochloride, the title compound was obtained in a yield of 79%in analogy to step 1 of example 15.

LC/MS (Method LC2): Rt=1.63 min; m/z=471.1 [MH⁺]

Step 52-{3-[2-(3-Cyano-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

From the compound of step 4, the title compound was obtained in a yieldof 37% by hydrolysis with lithium hydroxide in analogy to step 3 exceptthat the reaction was performed at room temperature.

¹H-NMR: δ=12.35 (br s, 1H); 8.61 (s, 1H); 7.84 (s, 1H); 7.72-7.68 (2d,2H); 7.54-7.49 (m, 2H); 7.43 (d, 1H); 7.24-7.20 (m, 2H); 7.18-7.13 (m,2H); 7.00 (d, 1H); 4.22 (t, 2H); 3.79 (s, 3H); 3.58 (d, 2H); 3.37 (d,2H); 3.11 (t, 2H)

EXAMPLE 952-{3-[2-(3-Carbamoyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

The compound of example 94 was reacted with lithium hydroxide at 60° C.for 50 min in analogy to step 3 of example 94. The obtained mixture ofthe title compound and2-{3-[2-(3-carboxy-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid (example 96) was separated by preparative RP HPLC (water/ACNgradient).

¹H-NMR: δ=12.3 (s, 1H); 8.61 (s, 1H); 7.91 (s, 1H); 7.83 (s, 1H); 7.72(d, 1H); 7.53-7.47 (m, 2H); 7.45 (d, 1H); 7.37 (t, 1H); 7.31 (s, 1H);7.23-7.19 (m, 2H); 7.17-7.12 (m, 2H); 7.00 (d, 1H); 4.22 (t, 2H); 3.78(s, 3H); 3.59 (d, 2H); 3.38 (d, 2H); 3.10 (t, 2H)

EXAMPLE 962-{3-[2-(3-Carboxy-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

The title compound was prepared as described in Example 95.

¹H-NMR: δ=13.0-12.2 (br, 2H); 8.62 (s, 1H); 7.94 (s, 1H); 7.80 (d, 1H);7.58 (d, 1H); 7.50 (dd, 1H); 7.47-7.42 (m, 2H); 7.22-7.19 (m, 2H);7.17-7.12 (m, 2H); 7.00 (d, 1H); 4.22 (t, 2H); 3.78 (s, 3H); 3.59 (d,2H); 3.37 (d, 2H); 3.12 (t, 2H)

EXAMPLE 975-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylicacid ethyl ester

(Benzhydrylidene-amino)-acetic acid ethyl ester (0.113 g, 0.414 mmol)was dissolved in DMF (3 ml) and cooled in an ice bath. Potassiumtert-butoxide (94.8 mg, 0.828 mmol) was added, and the mixture wasstirred for 10 min. The mixture was cooled to −30° C., and3,4-bis-chloromethyl-thiophene (50 mg, 0.276 mmol) was added in oneportion. The mixture was then placed into an ice bath again, and thereaction allowed to proceed for 20 min. The mixture was acidified with 2N hydrochloric acid, stirred for 10 min and partitioned between waterand diethyl ether. The aqueous phase was neutralized with a saturatedsodium hydrogencarbonate solution and extracted with EA. The combined EAextracts were washed with a saturated sodium chloride solution, driedover sodium sulfate, filtered and evaporated to dryness. The residue wasdissolved in diethyl ether, filtered, evaporated to dryness, acidifiedwith hydrogen chloride in methanol and evaporated to dryness. Theresidue was stirred with an diethyl ether/HEP mixture, and the solid wasfiltered and dried in vacuo to give crude5-amino-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid ethylester hydrochloride. A part of the crude compound (27 mg, 0.109 mmol)was reacted without further purification with4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 1 ofexample 15. After purification by preparative RP HPLC (water/ACNgradient), 23 mg of the title compound were obtained.

¹H-NMR: δ=8.78 (s, 1H); 7.50 (dd, 1H); 7.41 (d, 1H); 7.22-7.14 (m, 2H);7.11 (d, 1H); 7.08-6.99 (m, 4H); 4.18 (t, 2H); 4.05 (q, 2H); 3.80 (s,3H); 3.33 (d, 2H); 3.13 (d, 2H); 3.00 (t, 2H); 2.28 (s, 3H); 1.09 (t,3H)

EXAMPLE 985-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylicacid

The compound of example 97 (21 mg, 0.0438 mmol) was hydrolyzed inanalogy to step 3 of example 94. After evaporation to dryness, theresidue was stirred with diethyl ether, filtered and dried in vacuo togive 16 mg of the title compound.

¹H-NMR: δ=8.69 (s, 1H); 7.48 (d, 1H); 7.41 (s, 1H); 7.21-7.09 (m, 3H);7.05-6.98 (m, 4H); 4.19 (t, 2H); 3.80 (s, 3H); 3.30 (d, 2H); 3.11 (d,2H); 3.00 (t, 2H); 2.29 (s, 3H)

EXAMPLE 995-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylicacid

Starting from 2,3-bis-chloromethyl-thiophene, the title compound wasobtained in analogy to examples 97 and 98.

LC/MS (Method LC1): Rt=1.60 min; m/z=452.0 [MH⁺]

EXAMPLE 1002-Chloro-5-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylicacid

Step 1 5-Chloro-2,3-bis-chloromethyl-thiophene2,3-Bis-chloromethyl-thiophene (500 mg, 2.76 mmol) was dissolved inacetic acid (10 ml). Sulfuryl chloride (372 mg, 2.76 mmol) was added andthe mixture was stirred for 1 h at room temperature. The mixture waspartitioned between EA, water and an excess of solid sodiumhydrogencarbonate and the aqueous phase extracted with EA. The combinedorganic extracts were dried over magnesium sulfate, filtered andevaporated to dryness to give 240 mg of the title compound.

¹H-NMR: δ=7.13 (s, 1H); 5.16 (s, 2H); 4.76 (s, 2H)

Step 22-Chloro-5-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylicacid

From the compound of step 1, the title compound was obtained by reactionwith (benzhydrylidene-amino)-acetic acid ethyl ester in analogy toexample 97, step 1, reaction with 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoicacid in analogy to step 3 of example 1, and ester hydrolysis in analogyto example 2.

LC/MS (Method LC1): Rt=1.74 min; m/z=486.0/488.0 [MH⁺]

EXAMPLE 1016-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-6,7-dihydro-5H-[1]pyrindine-6-carboxylicacid

Step 16-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-6,7-dihydro-5H-[1]pyrindine-6-carboxylicacid ethyl ester

Isocyano-acetic acid methyl ester (112 mg, 1.13 mmol) and2,3-bis-chloromethyl-pyridine (200 mg, 1.14 mmol) were dissolved in DMF.Potassium tert-butoxide (0.255 g, 2.27 mmol) was added and the reactionmixture was stirred for 1 h at room temperature. The mixture waspartitioned between EA and a saturated aqueous sodium hydrogencarbonatesolution, the aqueous phase extracted with EA, and the organic extractswere dried over sodium sulfate, filtered and evaporated to dryness. Theresidue was purified by silica gel chromatography (HEP/EA gradient) togive 6-isocyano-6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid methylester. This compound was added to a solution of thionyl chloride (147mg, 1.23 mmol) in ethanol (1 ml) and refluxed overnight. The mixture wasevaporated to dryness, and the residue was stirred with HEP, filteredand dried in vacuo. The obtained product was reacted with4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 1 ofexample 15 and the title compound purified by preparative RP HPLC(water/ACN gradient).

LC/MS (Method LC1): Rt=1.22 min; m/z=475.2 [MH⁺]

Step 26-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-6,7-dihydro-5H-[1]pyrindine-6-carboxylicacid

The compound of step 1 was hydrolyzed with lithium hydroxide in analogyto step 3 of example 94 to give 5 mg of the title compound.

LC/MS (Method LC1): Rt=1.11 min; m/z=447.1 [MH⁺]

EXAMPLE 1022-{[5-Acetyl-4-(2-m-tolyl-ethoxy)-thiophene-2-carbonyl]-amino}-indane-2-carboxylicacid

The title compound was synthesized by reaction of5-acetyl-4-hydroxy-thiophene-2-carboxylic acid methyl ester with2-(3-methylphenyl)-ethanol in analogy to step 1 of example 1, subsequentester hydrolysis in analogy to example 2, reaction with2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogyto step 1 of example 15, and ester hydrolysis in analogy to example 2.

LC/MS (Method LC1): Rt=1.66 min; m/z=464.0 [MH⁺]

EXAMPLE 1032-{5-[2-(3-Chloro-phenyl)-ethoxy]-4-methoxy-2-nitro-benzoylamino}-indane-2-carboxylicacid

Step 1 5-[2-(3-Chloro-phenyl)-ethoxy]-4-methoxy-2-nitro-benzoic acidmethyl ester

Methyl 3-hydroxy-4-methoxybenzoate and 2-(3-chlorophenyl)-ethanol werereacted in analogy to step 1 of example 1. The obtained3-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoic acid methyl ester(0.750 g, 2.34 mmol) was added slowly to ice-cooled 100% nitric acid (10ml). The ice bath was removed and stirring was continued overnight. Themixture was cautiously transferred into a stirred mixture of EA, waterand an excess of sodium hydrogencarbonate and extracted with EA. Thecombined organic extracts were washed with a saturated sodium chloridesolution, dried over sodium sulfate, filtered and evaporated to dryness.The solid residue was extracted with diethyl ether, and the etherealsolution was evaporated. The residue was stirred with HEP, and the solidwas filtered and dried in vacuo to give 0.680 g of the title compound.

¹H-NMR: δ=7.63 (s, 1H); 7.45 (s, 1H); 7.37 (s, 1H); 7.37-7.27 (m, 3H);4.36 (t, 2H); 3.90 (s, 3H); 3.81 (s, 3H); 3.10 (t, 2H)

Step 22-{5-[2-(3-Chloro-phenyl)-ethoxy]-4-methoxy-2-nitro-benzoylamino}-indane-2-carboxylicacid

From the compound of step 1, the title compound was obtained byhydrolysis of the ester group in analogy to example 2, reaction of theobtained carboxylic acid with 2-amino-indane-2-carboxylic acid methylester hydrochloride in analogy to step 1 of example 15, and hydrolysisof the ester group in analogy to example 2.

¹H-NMR: δ=12.5 (s, 1H); 9.08 (s, 1H); 7.59 (s, 1H); 7.45 (s, 1H);7.38-7.28 (m, 3H); 7.25-7.20 (m, 2H); 7.18-7.12 (m, 2H); 6.97 (s, 1H);4.31 (t, 2H); 3.87 (s, 3H); 3.56 (d, 2H); 3.3 (d, 2H); 3.10 (t, 2H)

EXAMPLE 1042-{2-Bromo-5-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

Step 1 2-Bromo-5-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoic acidmethyl ester

Methyl 3-hydroxy-4-methoxybenzoate and 2-(3-chlorophenyl)-ethanol werereacted in analogy to step 1 of example 1. The obtained3-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoic acid methyl ester (300mg, 0.935 mmol) and sodium acetate (230 mg, 2.81 mmol) were dissolved inacetic acid (10 ml), bromine (224 mg, 1.40 mmol) was added, and themixture was stirred at 95° C. with reaction control every hour. When thereaction did no more proceed, further bromine was added. After 5 h thereaction was completed. The volatiles were evaporated in vacuo, theresidue was partitioned between EA and a saturated aqueous sodiumhydrogencarbonate solution, and the aqueous phase extracted with EA. Thecombined organic extracts were washed with a saturated sodium chloridesolution, dried over sodium sulfate, filtered and evaporated to dryness.This residue was purified by silica chromatography (HEP/EA gradient) togive 180 mg of the title compound.

¹H-NMR: δ=7.45-7.42 (m, 1H); 7.38 (s, 1H); 7.36-7.26 (m, 3H); 7.25 (s,1H); 4.21 (t, 2H); 3.85 (s, 3H); 3.80 (s, 3H); 3.04 (t, 2H)

Step 22-{2-Bromo-5-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

From the compound of step 1, the title compound was obtained byhydrolysis of the ester group in analogy to example 2, reaction of theobtained carboxylic acid with 2-amino-indane-2-carboxylic acid methylester hydrochloride in analogy to step 1 of example 15, and hydrolysisof the ester group in analogy to example 2.

LC/MS (Method LC1): Rt=1.64 min; m/z=544.0/546.0 [MH⁺]

EXAMPLE 1052-{2-Chloro-5-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

Step 1 2-Chloro-5-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoic acidmethyl ester

Methyl 3-hydroxy-4-methoxybenzoate and 2-(3-chlorophenyl)-ethanol werereacted in analogy to step 1 of example 1. The obtained3-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoic acid methyl ester (300mg, 0.935 mmol), N-chloro-succinimide (381 mg, 2.81 mmol), and zirconiumtetrachloride (129 mg, 0.57 mmol) were suspended in DCM (4 ml) and themixture was stirred under reflux for 5 h until the starting material wasused up. The mixture was partitioned between EA and a saturated aqueoussodium hydrogencarbonate solution, the aqueous phase extracted with EA,and the combined organic extracts were dried over sodium sulfate,filtered and evaporated to dryness. The residue was purified by silicachromatography (HEP/EA gradient) to give 118 mg of the title compound.

LC/MS (Method LC1): Rt=1.82 min; m/z=355.0/357.0 [MH⁺]

Step 22-{2-Chloro-5-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

From the compound of step 1, the title compound was obtained byhydrolysis of the ester group in analogy to example 2, reaction of theobtained carboxylic acid with 2-amino-indane-2-carboxylic acid methylester hydrochloride in analogy to step 1 of example 15, and hydrolysisof the ester group in analogy to example 2.

LC/MS (Method LC1): Rt=1.64 min; m/z=500.1/502.1 [MH⁺]

EXAMPLE 1062-[3-Fluoro-4-methoxy-5-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

Step 1 3-Acetoxy-5-amino-4-methoxy-benzoic acid

3-Acetoxy-4-methoxy-5-nitro-benzoic acid (4.50 g, 17.6 mmol) (R. T.Borchardt et al., J. Med. Chem. 25 (1982), 312-323; F. Tiemann et al.,Ber. dt. Chem. Ges. 9 (1876), 937) was dissolved in ethanol (180 ml) and0.5 M hydrogen chloride in methanol (4 ml) and hydrogenated in anH-Cube™ hydrogenation reactor with 100 bar hydrogen at 40° C. over a 10%palladium on charcoal cartridge. The mixture was evaporated to drynessto give 4.1 g of the title compound.

LC/MS (Method LC1): Rt=0.75 min; m/z=226.0 [MH⁺]

Step 2 3-Fluoro-5-hydroxy-4-methoxy-benzoic acid

The compound of step 1 (2.0 g, 8.88 mmol) was dissolved in aqueoustetrafluoroboric acid (48%, 4.5 ml), sodium nitrite (612 mg, 8.88 mmol)was added at 0° C., and the mixture was stirred at room temperature for60 min. The volatiles were evaporated, toluene was added to the oilyresidue and the mixture was heated at 100° C. for 4 h. The mixture waspartitioned between EA and 2 N hydrochloric acid, the aqueous phaseextracted with EA, and the combined organic extracts were dried oversodium chloride, decanted and evaporated to dryness. The residue waspurified by preparative RP HPLC (water/ACN gradient) to give 170 mg ofthe title compound.

¹H-NMR: δ=12.9 (br s, 1H); 10.1 (s, 1H); 7.29 (d, 1H); 7.18 (dd, 1H);3.85 (s, 3H)

Step 3 3-Acetoxy-5-fluoro-4-methoxy-benzoic acid

The compound of step 2 (169 mg, 913 mmol) was suspended in aceticanhydride (1.75 ml) and heated at 100° C. for 3 h. The solution wascooled, water (2 ml) was added, and the mixture was stirred at 60° C.for 1 h. Upon cooling, crystals formed which were filtered off and driedin vacuo to give 120 mg of the title compound.

¹H-NMR: δ=13 (br s, 1H); 7.67 (dd, 1H); 7.55 (d, 1H); 3.92 (s, 3H); 2.32(s, 3H)

Step 4 2-(3-Fluoro-5-hydroxy-4-methoxy-benzoylamino)-indane-2-carboxylicacid methyl ester

The compound of step 3 (120 mg, 0.526 mmol) was reacted with2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogyto step 1 of example 15. The obtained product was dissolved in methanol(0.77 ml), potassium carbonate (2 mg) was added, and the mixture wasstirred at room temperature for 30 min. The solvent was evaporated, theresidue was partitioned between EA and a saturated sodium chloridesolution, and the aqueous phase extracted with EA. The combined organicextracts were dried over sodium sulfate, filtered and evaporated todryness to give 60 mg of the title compound.

LC/MS (Method LC1): Rt=1.35 min; m/z=360.0 [MH⁺]

Step 52-[3-Fluoro-4-methoxy-5-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

From the compound of step 4, the title compound was obtained by reactionwith 2-(3-methylphenyl)-ethanol in analogy to step 1 of example 1 andhydrolysis in analogy to example 2.

¹H-NMR: δ=12.4 (br s, 1H); 8.76 (s, 1H); 7.92-7.84 (m, 2H); 7.25-7.09(m, 7H); 7.03 (d, 1H); 4.27 (t, 2H); 3.73 (s, 3H); 3.60 (d, 2H); 3.37(d, 2H); 3.05 (t, 2H); 2.28 (s, 3H)

EXAMPLE 1072-[4-Methoxy-3-nitro-5-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The title compound was obtained from 3-acetoxy-4-methoxy-5-nitro-benzoicacid by reaction with 2-amino-indane-2-carboxylic acid methyl esterhydrochloride, hydrolysis of the acetoxy group in analogy to step 4 ofexample 106, and reaction of the obtained product with2-(3-methylphenyl)-ethanol and subsequent ester hydrolysis in analogy tostep 5 of example 106.

LC/MS (Method LC1): Rt=1.77 min; m/z=491.0 [MH⁺]

EXAMPLE 1082-{[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoyl]-methyl-amino}-indane-2-carboxylicacid

Step 1 1,3-Dimethyl-spiro(imidazolidin-5,2′-indane)-2,4-dione

Spiro[imidazolidine-4,2′-indane]-2,5-dione (2-indanone hydantoin) (200mg, 0.989 mmol) and potassium tert-butoxide (255 mg, 2.28 mmol) weresuspended in DMF (2 ml) and stirred for 20 min at room temperature.Iodomethane (323 mg, 2.28 mmol) was added and the mixture was stirredovernight. The addition of potassium tert-butoxide, stirring for 20 min,addition of iodomethane and stirring overnight at room temperature wererepeated. Then the reaction mixture was partitioned between EA and 2 Nhydrochloric acid, the aqueous phase extracted with EA, and the combinedorganic extracts were dried over sodium chloride, decanted andevaporated to dryness. Purification of the residue by silica gelchromatography gave a mixture of the mono-methylated and thedi-methylated product. This mixture was dissolved in a 3:1 mixture of0.3 N potassium hydroxide solution and dioxane and stirred overnight atroom temperature. The mixture was partitioned between EA and water andthe aqueous phase extracted with EA. The combined organic extracts weredried over sodium chloride, decanted and evaporated to dryness to give90 mg of the title compound.

LC/MS (Method LC1): Rt=1.10 min; m/z=231.1 [MH⁺]

Step 22-{[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoyl]-methyl-amino}-indane-2-carboxylicacid

The compound of step 1 (90 mg, 0.391 mmol) was dissolved in a mixture ofmethanol and 50% sodium hydroxide solution and stirred in a microwavereactor at 140° C. for about 3 h until hydrolysis was complete. Themixture was evaporated to dryness and the residue suspended in a mixtureof water (6 ml) and dioxane (3 ml) and cooled in an ice bath. An excessof 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoyl chloride, which had beenfreshly prepared by dissolving the corresponding benzoic acid in thionylchloride, stirring the mixture at 60° C. for 20 min, evaporating todryness and dissolving the residue in dioxane, was slowly added to themixture with stirring. The reaction mixture was stirred for 1 h in theice bath. Then the mixture was partitioned between 2 N hydrochloric acidand EA, the aqueous phase extracted with EA, and the combined organicextracts were dried over sodium chloride, decanted and evaporated todryness in vacuo. The residue was purified by silica gel chromatography(DCM/methanol/ammonium hydroxide gradient).

¹H-NMR: δ=12.3 (br s, 1H); 7.25-7.08 (m, 7H); 7.05-6.97 (m, 4H); 4.15(t, 2H); 3.79 (s, 3H); 3.63 (d, 2H); 3.40 (d, 2H); 3.00 (t, 2H); 2.98(s, 3H); 2.27 (s, 3H)

EXAMPLE 1092-(3-Benzenesulfonyloxy-4-methoxy-benzoylamino)-indane-2-carboxylic acid

The compound of step 2 of example 15 (200 mg, 0.586 mmol) was dissolvedin ACN (3 ml), potassium carbonate (243 mg, 1.7 mmol) andbenzenesulfonyl chloride (155 mg, 0.88 mmol) were added, and the mixturewas stirred for 30 min. The mixture was partitioned between EA andsaturated sodium chloride solution, the aqueous phase extracted with EA,and the combined organic extracts were dried over magnesium sulfate,filtered, and evaporated to dryness. The residue was dissolved indioxane (0.8 ml), lithium hydroxide (0.8 ml of a 1 N aqueous solution)was added, and the mixture was stirred at room temperature for 2.5 h.The mixture was partitioned between 2 N hydrochloric acid and EA, theaqueous phase extracted with EA, and the combined organic extracts weredried over magnesium sulfate, filtered and evaporated to dryness. Theresidue was purified by preparative RP HPLC (water/ACN gradient) to give115 mg of the title compound.

¹H-NMR: δ=12.4 (s, 1H); 8.77 (s, 1H); 7.87-7.77 (m, 4H); 7.72 (d, 1H);7.67-7.61 (m, 2H); 7.76-7.71 (m, 2H); 7.21-7.16 (m, 2H); 7.10 (d, 1H);3.57 (d, 2H); 3.48 (s, 3H); 3.38 (d, 2H)

In analogy to example 109, the example compounds of the formula Inlisted in table 2 were prepared. The compounds can be named as2-[3-(R⁹¹-sulfonyloxy)-4-methoxy-benzoylamino]-indane-2-carboxylic acid,for example as2-[3-(toluene-3-sulfonyloxy)-4-methoxy-benzoylamino]-indane-2-carboxylicacid in the case of example 111.

TABLE 2 Example compounds of the formula In m/z Retention Example R⁹¹LC/MS Method [MH⁺] time [min] 110 4-methyl-phenyl LC2 482.0 1.54 1113-methyl-phenyl LC2 482.0 1.54 112 2-methyl-phenyl LC2 482.0 1.55

EXAMPLE 1132-[4-Methoxy-3-(2-m-tolyloxy-acetyl)-benzoylamino]-indane-2-carboxylicacid

Step 1 3-(2-Bromo-acetyl)-4-methoxy-benzoic acid methyl ester

3-Acetyl-4-methoxy-benzoic acid methyl ester (T. Nagano et al., J. Am.Chem. Soc. 75 (1953), 6237-6238) (1.25 g) was dissolved in a mixture ofacetic acid (7 ml) and hydrobromic acid (3 ml), the solution was cooledin an ice bath, and bromine (0.961 g) added. The mixture was allowed toslowly warm to room temperature and react for 2 h. Then the mixture wasevaporated to dryness in vacuo, the residue was partitioned between EAand a saturated aqueous sodium hydrogencarbonate solution, the aqueousphase extracted with EA, and the combined organic extracts were driedover sodium sulfate, filtered and evaporated to dryness. Upon stirringwith a mixture of EA and HEP, part of the title compound crystallizedand was filtered off. The filtrate was evaporated to dryness and theresidue purified by preparative RP HPLC (water/ACN gradient).Altogether, 1.18 g of the title compound were obtained.

LC/MS (Method LC2): Rt=1.40 min; m/z=287.0/289.0 [MH⁺]

Step 2 4-Methoxy-3-(2-m-tolyloxy-acetyl)-benzoic acid methyl ester

The compound of step 1 (1.18 g, 4.12 mmol) and potassium carbonate (1.72g, 12.4 mmol) were suspended in DMF (10 ml), m-cresol (450 mg, 4.12mmol) was added, and the mixture was stirred at room temperature for 2h. The volatiles were evaporated in vacuo, the residue was partitionedbetween EA and water, and the aqueous phase extracted with EA. Thecombined organic extracts were washed with a sodium chloride solution,dried over sodium sulfate, filtered and evaporated to dryness. Theresidue was purified by preparative RP HPLC (water/ACN gradient) to give0.49 g of the title compound.

¹H-NMR: δ=8.28 (d, 1H); 8.18 (dd, 1H); 7.37 (d, 1H); 7.13 (dd, 1H); 6.74(d, 1H); 6.72 (s, 1H); 6.67 (d, 1H); 5.30 (s, 2H); 4.03 (s, 3H); 3.85(s, 3H); 2.26 (s, 3H)

Step 32-[4-Methoxy-3-(2-m-tolyloxy-acetyl)-benzoylamino]-indane-2-carboxylicacid

From the compound of step 2, the title compound was obtained byhydrolysis of the ester group in analogy to example 2, reaction of theobtained carboxylic acid with 2-amino-indane-2-carboxylic acid methylester hydrochloride in analogy to step 1 of example 15, and hydrolysisof the ester group in analogy to example 2.

¹H-NMR: δ=12.4 (s, 1H); 8.88 (s, 1H); 8.22 (d, 1H); 8.10 (dd, 1H); 7.29(d, 1H); 7.23-7.19 (m, 2H); 7.18-7.10 (m, 3H); 6.73 (d, 1H); 6.70 (s,1H); 6.65 (d, 1H); 5.28 (s, 2H); 3.98 (s, 3H); 3.57 (d, 2H); 3.40 (d,2H); 2.24 (s, 3H)

EXAMPLE 1142-[3-(1-Hydroxy-2-m-tolyloxy-ethyl)-4-methoxy-benzoylamino]-indane-2-carboxylicacid

The compound of example 113 (113 mg, 0.246 mmol) was dissolved in amixture of methanol (2 ml) and ethanol (2 ml). With cooling in an icebath, sodium borohydride (28 mg, 0.738 mmol) was added to the stirredsolution, and the mixture was stirred in an ice bath for 2 h. Thevolatiles were evaporated, the residue was partitioned between diethylether and diluted hydrochloric acid, the aqueous phase extracted withdiethyl ether, the combined organic extracts filtered over a small plugof silica gel, dried with sodium sulfate, filtered and evaporated todryness. The residue was stirred with a mixture of EA and HEP andfiltered to give 112 mg of the title compound.

LC/MS (Method LC2): Rt=1.51 min; m/z=462.1 [MH⁺]

EXAMPLE 1152-[4-Methoxy-3-(2-m-tolyloxy-ethyl)-benzoylamino]-indane-2-carboxylicacid

The compound of example 114 (20 mg, 0.043 mmol) was dissolved in ethanol(2 ml), a 0.5 M solution of hydrogen chloride in methanol (0.2 ml) wasadded and the mixture was hydrogenated overnight in the presence ofpalladium on charcoal (10%) at room temperature at a hydrogen pressureof 5 bar (complete conversion of the starting compound). Afterfiltration over a small plug of silica gel and evaporation, the residuewas purified by preparative RP HPLC (water/ACN gradient).

LC/MS (Method LC2): Rt=1.69 min; m/z=446.0 [MH⁺]

EXAMPLE 1162-[4-Methoxy-3-(3-m-tolyl-propyl)-benzoylamino]-indane-2-carboxylic acid

Step 1 3-(1,3-Dihydroxy-3-m-tolyl-propyl)-4-methoxy-benzoic acid methylester

3-Acetyl-4-methoxy-benzoic acid methyl ester (150 mg, 0.720 mmol) wasdissolved in THF (3 ml), cooled to −78° C., and a freshly preparedsolution of lithium diisopropylamide (obtained by addition ofn-butyllithium in n-hexane (0.317 ml, 2.5 M solution) todiisopropylamine (80.1 mg, 0.792 mmol) in THF (3 ml) at 0° C. andstirring for 10 min) was slowly added with stirring. After 10 min,3-methylbenzaldehyde (86.5 mg, 0.720 mmol) was added at −78° C. After 30min at −78° C., 2 N hydrochloric acid and EA were added, the coolingbath was removed, the mixture was brought to room temperature. Thephases were separated, the aqueous phase was extracted three times withEA, the combined organic extracts were dried over sodium chloride,decanted and evaporated to dryness. The residue was dissolved inmethanol (5 ml), sodium borohydride (28.7 mg, 0.761 mmol) was added, andthe mixture was stirred at room temperature for 30 min. The mixture wasevaporated to dryness and the residue was purified by silica gelchromatography (HEP/EA gradient) to give 140 mg of the title compound asa mixture of diastereomers.

LC/MS (Method LC1): Rt=1.32 min; m/z=353.1 [MNa⁺], 683.2 [2MNa⁺]

Step 2 4-Methoxy-3-(3-m-tolyl-propyl)-benzoic acid methyl ester

The compound of step 1 (140 mg, 0.424 mmol) was dissolved in ethanol (10ml) and 12 N hydrochloric acid (0.2 ml), palladium on charcoal (10%) wasadded, and the mixture was hydrogenated at a hydrogen pressure of 6 barat room temperature overnight. After filtration and evaporation, theresidue was purified by silica gel chromatography (HEP/EA gradient) togive 80 mg of the title compound.

¹H-NMR: δ=7.83 (dd, 1H); 7.72 (d, 1H); 7.16 (dd, 1H); 7.06 (d, 1H);7.03-6.96 (m, 3H); 3.85 (s, 3H); 3.80 (s, 3H); 2.65-2.53 (m, 4H); 2.27(s, 3H); 1.82 (m, 2H)

Step 32-[4-Methoxy-3-(3-m-tolyl-propyl)-benzoylamino]-indane-2-carboxylic acid

From the compound of step 2, the title compound was obtained byhydrolysis of the ester group in analogy to example 2, reaction of theobtained carboxylic acid with 2-amino-indane-2-carboxylic acid methylester hydrochloride in analogy to step 1 of example 15, and hydrolysisof the ester group in analogy to example 2.

¹H-NMR: δ=12.3 (br s, 1H); 8.61 (s, 1H); 7.73 (dd, 1H); 7.66 (d, 1H);7.25-7.20 (m, 2H); 7.19-7.12 (m, 3H); 3.81 (s, 3H); 3.57 (d, 2H); 3.38(d, 2H); 2.61-2.52 (m, 4H); 2.26 (s, 3H); 1.86-1.78 (m, 2H)

EXAMPLE 1172-(4-Methoxy-3-phenylacetylamino-benzoylamino)-indane-2-carboxylic acid

Step 1 2-(4-Methoxy-3-nitro-benzoylamino)-indane-2-carboxylic acidmethyl ester

To 2-amino-indane-2-carboxylic acid methyl ester hydrochloride (0.40 g,1.77 mmol) and 4-methoxy-3-nitrobenzoic acid (0.35 g, 1.77 mmol) in 4 mlof DMF were added NMM (0.59 ml, 5.32 mmol), HOBT (0.31 g, 2.31 mmol) andEDC (0.44 g, 2.31 mmol). The mixture was stirred at 60° C. until LC/MSanalysis showed complete conversion. The crude product was purified bysilica gel chromatography (HEP/EA gradient) to give 0.43 g of the titlecompound.

Step 2 2-(3-Amino-4-methoxy-benzoylamino)-indane-2-carboxylic acidmethyl ester

The compound of step 1 (0.43 g, 1.16 mmol) was dissolved in methanol (30ml), 10% palladium on charcoal (200 mg) was added, and the flask flushedwith argon. A balloon filled with hydrogen was connected, and themixture was stirred at room temperature overnight. The balloon wasremoved, the flask flushed with argon, the catalyst filtered off overCelite, and the filtrate was evaporated in vacuo to give 0.38 g of thetitle compound.

Step 32-(4-Methoxy-3-phenylacetylamino-benzoylamino)-indane-2-carboxylic acidmethyl ester

The compound of step 2 (0.042 g, 0.12 mmol) and phenylacetic acid (0.013g, 0.092 mmol) were dissolved in DCM (3 ml) and DMF (1 ml), NMM (0.031ml, 0.28 mmol), HOBT (0.016 g, 0.12 mmol) and EDC (0.021 g, 0.12 mmol)were added, and the mixture was stirred overnight. LC/MS analysis showedcomplete conversion. The mixture was filtered, the filtrate subjected topreparative RP HPLC (water/ACN gradient), and the fractions containingthe title compound freeze-dried. Yield: 0.042 g.

Step 42-(4-Methoxy-3-phenylacetylamino-benzoylamino)-indane-2-carboxylic acid

The compound of step 3 (42 mg, 0.091 mmol) was dissolved in methanol (3ml) and water (1 ml), lithium hydroxide hydrate (5.3 mg, 0.12 mmol) wasadded, and the mixture was reacted at room temperature overnight. LC/MSanalysis showed complete conversion. The mixture was filtered, thefiltrate subjected to preparative RP HPLC (water/ACN gradient), and thefractions containing the title compound freeze-dried. Yield: 27 mg.

LC/MS (Method LC5): Rt=1.95 min; m/z=445.48 [MH⁺]

¹H-NMR: δ=12.4 (br s, 1H); 9.39 (s, 1H); 8.67 (s, 1H); 8.31 (s, 1H);7.62 (d, 1H); 7.38-7.30 (m, 4H); 7.28-7.20 (m, 3H); 7.18-7.12 (m, 2H);7.08 (d, 1H); 3.87 (s, 3H); 3.72 (s, 2H); 3.55 (d, 2H); 3.35 (d, 2H)

In analogy to example 117, the example compounds of the formula Iplisted in table 3 were prepared. The compounds can be named as2-[3-(R⁹²-carbonyl-amino)-4-methoxy-benzoylamino)-indane-2-carboxylicacid, for example as2-[3-[3-fluoro-benzoylamino)-4-methoxy-benzoylamino)-indane-2-carboxylicacid in the case of example 120.

TABLE 3 Example compounds of the formula Ip m/z Retention Example R⁹²LC/MS Method [MH⁺] time [min] 118 3-bromo-benzyl LC6 523.04 1.75 1193-chloro-benzyl LC6 479.08 1.72 120 3-fluoro-phenyl LC6 449.12 1.66

EXAMPLE 1212-[3-(4-Fluoro-benzylamino)-4-methoxy-benzoylamino]-indane-2-carboxylicacid

Step 12-[3-(4-Fluoro-benzylamino)-4-methoxy-benzoylamino]-indane-2-carboxylicacid methyl ester

The compound of example 117, step 2 (0.042 g, 0.12 mmol) and4-fluorobenzaldehyde (0.0115 g, 0.092 mmol) were dissolved in THF (3 ml)and acetic acid (0.5 ml). Resin-bound sodium cyanoborohydride (0.2 mmol)was added, and the mixture was stirred at room temperature until LC/MSanalysis showed complete conversion. The resin was filtered off, thefiltrate was subjected to preparative RP HPLC (water/ACN gradient), andthe fractions containing the title compound freeze-dried to give 33 mgof the title compound.

Step 22-[3-(4-Fluoro-benzylamino)-4-methoxy-benzoylamino]-indane-2-carboxylicacid

The compound of step 1 (30 mg, 0.053 mmol) was dissolved in methanol (3ml) and water (1 ml). Lithium hydroxide hydrate (3.8 mg, 0.09 mmol) wasadded, and the mixture was stirred at room temperature until LC/MSanalysis showed complete conversion. The mixture was filtered, thefiltrate subjected to preparative RP HPLC (water/ACN gradient), and thefractions containing the title compound freeze-dried to give 19 mg ofthe title compound.

LC/MS (Method LC6): Rt=1.66 min; m/z=435.19 [MH⁺]

¹H-NMR: δ=12.2 (br s, 1H); 8.45 (s, 1H); 7.38-7.32 (m, 2H); 7.22-7.20(m, 2H); 7.20-7.14 (m, 3H); 7.14-7.09 (m, 2H); 6.92 (s, 1H); 6.81 (d,1H); 4.32 (s, 2H); 3.80 (s, 3H); 3.72 (s, 2H); 3.53 (d, 2H); 3.32 (d,2H)

In analogy to example 121, the example compounds of the formula Irlisted in table 4 were prepared. The compounds can be named as2-[3-(R⁹³-amino)-4-methoxy-benzoylamino]-indane-2-carboxylic acid, forexample as2-[3-[2-phenyl-ethylamino)-4-methoxy-benzoylamino)-indane-2-carboxylicacid in the case of example 122.

TABLE 4 Example compounds of the formula Ir m/z Retention Example R⁹³LC/MS Method [MH⁺] time [min] 122 2-phenyl-ethyl LC6 431.13 1.61 1233-chloro-benzyl LC6 451.07 1.79 124 2-phenyl-propyl LC6 445.13 1.76

EXAMPLE 125 General Procedure for Solid Phase Synthesis

0.5 g of Polystyrene AM RAM resin with FMOC-protected linker (0.5 mmol/gor 0.75 mmol/g, respectively; Rapp Polymere GmbH, Tubingen, Germany)were treated with a 50% solution of piperidine in DMF for 20 min andwashed extensively with DMF. The respective FMOC-protected2-amino-indane-2-carboxylic acid (5 equivalents), HOBT (5 equivalents)and DIC (5 equivalents) were dissolved in DMF (5 ml) and added to theresin. The mixture was shaken overnight at room temperature. The resinwas repeatedly washed with DMF and the FMOC protecting group was removedby treatment of the resin with a 50% solution of piperidine in DMF for20 min. The resin was repeatedly washed with DMF.

For acylation of the amino group, a solution of the respectivehydroxy-substituted benzoic acid (5 equivalents), HOBT (5 equivalents)and DIC (5 equivalents) in DMF (5 ml) was added to the resin and themixture was shaken overnight at room temperature. The resin was washedwith DMF and treated with a 2 N solution of dimethylamine in THFovernight, or in some cases with a 50% solution of piperidine in DMF for2 h, for hydrolyzing the ester formed by acylation of the hydroxy group.The resin was washed extensively with DMF, DCM and THF.

For the Mitsunobu reaction on the hydroxy group, triphenylphosphine (10equivalents) and the respective alcohol (10 equivalents) were dissolvedin 5 ml of dry THF and added to the resin. The slurry was cooled to 0°C. and DIAD (10 equivalents) was added to the cooled mixture which wasallowed to react overnight at room temperature. The resin was washedrepeatedly with DCM.

For cleavage of the obtained compound, the resin was treated with neatTFA for 2 h. TFA was removed in vacuo, and the residue was purified bypreparative RP HPLC (water/ACN gradient). In most cases the carboxylicacid was isolated after the TFA cleavage. In some cases the carboxylicacid amide was isolated which was converted into the carboxylic acid byhydrolysis in 50% aqueous TFA at 60° C. overnight, partial removal ofthe TFA in vacuo and lyophilization of the aqueous solution.

According to the general procedure described in example 125, thecompounds of the formula Is listed in table 5 were synthesized. In theformulae of the groups R⁹⁵ in table 5 the line crossed with the symbol

represents the free bond via which the group R⁹⁵ is bonded to the oxygenatom which is attached to the 3-position of the benzoyl group depictedin formula Is. I.e., in the formula of the complete molecule theterminal endpoint of the line crossed with the said symbol ends at theoxygen atom attached to the 3-position of the benzoyl group. Thecompounds can be named as2-[3-(R⁹⁵-oxy)-4-R⁹⁴-benzoylamino]-indane-2-carboxylic acid, for exampleas2-{4-methoxy-3-[2-(3-trifluoromethyl-phenyl)-ethoxy]-benzoylamino}-indane-2-carboxylicacid in the case of example 127.

TABLE 5 Example compounds of the formula Is       Example       R⁹⁴—

    LC/MS Method     m/z [MH⁺]     Retention time [min] 126 CH₃O—

LC9 432.2 4.32 127 CH₃O—

LC8 500.2 4.39 128 Cl—

LC8 504.1/ 506.1 4.80 129 CH₃—

LC9 430.2 5.14 130 CH₃O—

LC9 432.2 4.51 131 CH₃O—

LC9 450.2 4.58 132 CH₃O—

LC9 466.1/ 468.1 4.74 133 CH₃O—

LC9 462.2 4.48 134 CH₃O—

LC9 446.2 4.65 135 CH₃O—

LC9 446.2 4.69 136 CH₃O—

LC9 450.2 4.55 137 CH₃O—

LC9 462.2 4.48 138 CH₃O—

LC9 462.2 4.57 139 CH₃O—

LC9 450.2 4.55 140 CH₃O—

LC9 460.2 4.91 141 H—

LC7 416.2 4.50 142 CH₃O—

LC7 446.2 4.56 143 CH₃O—

LC7 510.1/ 512.1 5.28 144 CH₃O—

LC7 446.2 5.14 145 F—

LC7 434.2 4.89 146 CH₃O—

LC7 438.1 4.35 147 CH₃O—

LC7 438.1 4.34 148 CH₃O—

LC7 433.2 2.56 149 CH₃O—

LC7 466.1/ 468.1 4.64 150 CH₃O—

LC7 424.2 4.72 151 CH₃O—

LC7 446.2 4.58 152 CH₃O—

LC9 484.1/ 486.1 4.71 153 CH₃O—

LC9 484.1/ 486.1 4.77 154 CH₃O—

LC9 518.2 4.86 155 CH₃O—

LC9 518.2 8.87

EXAMPLE 1565-Bromo-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The title compound was prepared according to the general proceduredescribed in example 125.

LC/MS (Method LC7): Rt=5.06 min; m/z=524.1/526.1 [MH⁺]

EXAMPLE 1575-Fluoro-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The title compound was prepared according to the general proceduredescribed in example 125.

LC/MS (Method LC7): Rt=4.74 min; m/z=464.2 [MH⁺]

EXAMPLE 1582-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dimethyl-indane-2-carboxylicacid

The title compound was prepared according to the general proceduredescribed in example 125.

LC/MS (Method LC7): Rt=5.03 min; m/z=474.2 [MH⁺]

EXAMPLE 1595-Methoxy-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The title compound was prepared according to the general proceduredescribed in example 125.

LC/MS (Method LC7): Rt=4.60 min; m/z=476.2 [MH⁺]

EXAMPLE 1602-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acidamide

The compound of example 14 (100 mg, 0.224 mmol) was added to thionylchloride (0.5 ml) and stirred for 30 min at 60° C. The volatiles wereevaporated, dioxane (1 ml) was added and the mixture was evaporated todryness again. The obtained raw acid chloride was dissolved in DCM andadded to a stirred mixture of EA, a saturated sodium hydrogencarbonatesolution and ammonia (30% in water, 0.015 ml). After stirring at roomtemperature for 90 min, the layers were separated and the aqueous layerwas extracted with EA. The combined organic extracts were dried oversodium sulfate and evaporated to dryness. The residue was purified bypreparative RP HPLC (water/ACN gradient).

LC/MS (Method LC1): Rt=1.55 min; m/z=445.1 [MH⁺]

EXAMPLE 1612-{4-[2-(3-Chloro-phenyl)-ethoxy]-3-methoxy-benzoylamino}-indane-2-carboxylicacid

The title compound was prepared according to the general proceduredescribed in example 125.

LC/MS (Method LC7): Rt=4.70 min; m/z=466.1/468.1 [MH⁺]

EXAMPLE 1622-{4-[2-(2-Chloro-phenyl)-ethoxy]-3-methoxy-benzoylamino}-indane-2-carboxylicacid

The title compound was prepared according to the general proceduredescribed in example 125.

LC/MS (Method LC7): Rt=4.69 min; m/z=466.1/468.1 [MH⁺]

EXAMPLE 1632-[4-Amino-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid

The title compound was prepared according to the general proceduredescribed in example 125 using 0.1 g of resin (0.5 mmol/g). In theacylation step, 3-hydroxy-4-nitro-benzoic acid was employed. In thefinal step the nitro group was reduced with a 1 M solution of tin(II)chloride dihydrate in DMF overnight at room temperature. The resin waswashed extensively with DMF, methanol, and DCM, and the product wascleaved from the resin by treatment with TFA for 2 h. TFA was removed invacuo, and the residue was purified by preparative RP HPLC (water/ACNgradient). Yield: 12.4 mg.

LC/MS (Method LC9): Rt=4.33 min; m/z=431.2 [MH⁺]

¹H-NMR (300 MHz, D₆-DMSO+2% TFA): δ=2.29 (s, 3H); 3.06 (t, J=6.97 Hz,2H); 3.30-3.43 (m, 2H); 3.54-3.65 (m, 2H); 4.28 (t, J=7.06 Hz, 2H); 7.04(d, J=7.35 Hz, 1H); 7.09-7.26 (m, 8H); 7.43-7.54 (m, 2H); 8.71 (s, 1H)

EXAMPLE 1642-[4-Methylamino-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The title compound was prepared in analogy to example 163 using 0.12 gof resin (0.5 mmol/g). After reduction of the nitro group, the aminogroup was methylated using a 37% aqueous formaldehyde solution (10equivalents) and sodium cyanoborohydride (8 equivalents, 1 M solution inTHF) in a mixture of DCM and ACN (3:1) containing 2% of acetic acid. Themixture was shaken overnight, then the resin was washed and theprocedure was repeated with fresh reagents. For cleavage, the resin wastreated with TFA for 2 h, TFA was removed in vacuo and the residue wasdissolved in 50% aqueous TFA. The solution was heated to 50° C. for 48h, TFA was partially removed in vacuo and the aqueous solution waslyophilized. The residue was purified by preparative RP HPLC (water/ACNgradient). Yield: 9.8 mg.

LC/MS (Method LC7): Rt=4.41 min; m/z=445.2 [MH⁺]

¹H-NMR (300 MHz, D₆-DMSO+2% TFA): δ=2.28 (s, 3H); 2.75 (s, 3H); 3.04 (t,J=6.78 Hz, 2H); 3.30-3.41 (m, 2H); 3.52-3.63 (m, 2H); 4.21 (t, J=6.88Hz, 2H); 6.61-6.71 (m, 1H); 7.03 (d, J=7.16 Hz, 1H); 7.10-7.25 (m, 7H);7.37 (d, J=1.70 Hz, 1H); 7.47 (dd, J=8.19/1.79 Hz, 1H); 8.49 (br s, 1H)

EXAMPLE 1652-[4-Dimethylamino-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The title compound was prepared in analogy to example 164 using 0.12 gof resin (0.5 mmol/g) and repeating the methylation procedure three moretimes with fresh reagents for complete conversion of intermediarymethylamino compound into the dimethylamino compound. Yield: 6.6 mg.

LC/MS (Method LC7): Rt=3.37 min; m/z=459.2 [MH⁺]

¹H-NMR (300 MHz, D₆-DMSO+2% TFA): δ=2.28 (s, 3H); 3.04 (s, 6H); 3.12 (t,J=6.50 Hz, 2H); 3.33-3.44 (m, 2H); 3.62 (d, J=16.77 Hz, 2H); 4.43 (t,J=6.69 Hz, 2H); 7.04 (d, J=6.97 Hz, 1H); 7.11-7.27 (m, 7H); 7.55-7.71(m, 3H); 8.93 (s, 1H)

EXAMPLE 1662-[4-Isopropylamino-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The title compound was prepared in analogy to example 163 using 0.25 gof resin (0.5 mmol/g). After reduction of the nitro group, the aminogroup was alkylated using 2-methoxypropene (10 equivalents) in 2 ml of amixture of DCM and ACN (3:1) containing 2% of acetic acid and 1 ml of a1 M solution of sodium cyanoborohydride in THF. The alkylation wasrepeated three times with fresh reagents. Cleavage and work-up wereperformed in analogy to example 164. Yield: 13.4 mg.

LC/MS (Method LC7): Rt=4.19 min; m/z=473.2 [MH⁺]

EXAMPLE 1672-{3-[2-(2-Fluoro-phenyl)-2-hydroxy-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

The title compound was prepared according to the general proceduredescribed in example 125 using 0.25 g of resin (0.5 mmol/g). Attachmentof the 2-amino-indane-2-carboxylic acid moiety to the resin was followedby acylation with 3-hydroxy-4-methoxy-benzoic acid and treatment with50% piperidine in DMF for 2 h. After extensive washing with DMF and DCMthe resin was reacted with 2-bromo-1-(2-fluoro-phenyl)-ethanone (3equivalents) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU;3 equivalents) in 3 ml of DCM overnight at room temperature. Thecompound was cleaved from the resin with neat TFA for 2 h, and TFA wasevaporated in vacuo. The crude intermediate product was dissolved in 4ml of THF, 10 mg of lithium borohydride were added and the reactionmixture was shaken for 3 h. Then the reaction mixture was quenched withacetic acid, evaporated to dryness, and the residue was purified bypreparative RP HPLC (water/ACN gradient). Yield: 3.7 mg.

LC/MS (Method LC7): Rt=4.01 min; m/z=466.2 [MH⁺]

EXAMPLE 1682-[4-Cyano-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid

The title compound was prepared according to the general proceduredescribed in example 125 using 0.3 g of resin (0.75 mmol/g).3-Hydroxy-4-iodo-benzoic acid was used in the acylation step. Finally,the resin with the iodo compound was treated with zinc cyanide andtetrakis(triphenylphosphine)palladium(0) in 5 ml of DMF/EDIA (2:1) in amicrowave reactor (90 W) at 150° C. for 10 min. The resin was decantedwith DCM, then extensively washed with DMF and DCM, and the product wascleaved with neat TFA for 2 h. TFA was removed in vacuo, and the residuewas dissolved in 50% aqueous TFA and heated at 50° C. overnight. The TFAwas partially evaporated and the aqueous solution was lyophilized. Thecompound was purified by preparative RP HPLC (water/ACN gradient).Yield: 11.4 mg.

LC/MS (Method LC7): Rt=4.78 min; m/z=441.2 [MH⁺]

¹H-NMR (300 MHz, D₆-DMSO+2% TFA): δ=2.28 (s, 3H); 3.05 (t, J=6.69 Hz,2H); 3.33-3.43 (m, 2H); 3.55-3.65 (m, 2H); 4.36 (t, J=6.59 Hz, 2H); 7.03(d, J=7.16 Hz, 1H); 7.09-7.26 (m, 7H); 7.49-7.58 (m, 2H); 7.80 (d,J=7.91 Hz, 1H); 9.04 (s, 1H)

EXAMPLE 1692-[4-Methoxy-3-(3-phenyl-propyl)-benzoylamino]-indane-2-carboxylic acid

The title compound was prepared according to the general proceduredescribed in example 125 using 0.3 g of resin (0.75 mmol/g).3-Iodo-4-methoxy-benzoic acid was used as the acylation agent in placeof the hydroxy-substituted benzoic acid. Finally, the resin with theiodo compound was reacted under Sonogashira conditions with3-phenyl-1-propyne (10 equivalents) dissolved in 4 ml of DMF togetherwith triethylamine (20 equivalents), copper(I) iodide (0.1 equivalents)and bis(triphenylphosphine)palladium(II) chloride (0.1 equivalents). Thereaction mixture was shaken at room temperature for 48 h. The resin waswashed with DMF, DCM and the intermediate product was cleaved with neatTFA for 2 h. TFA was removed in vacuo, and residue was dissolved inwater/ACN (3:2) and lyophilized. The isolated intermediate product wasdissolved in 6 ml of methanol, 100 mg of 10% palladium on charcoal wereadded, and the mixture was hydrogenated in a Parr reactor at about 3.5bar for 2 h. After filtration, methanol was evaporated and the residuewas purified by preparative RP HPLC (water/ACN gradient). Yield: 13.7mg.

LC/MS (Method LC7): Rt=4.97 min; m/z=430.2 [MH⁺]

¹H-NMR (300 MHz, D₆-DMSO+2% TFA): δ=1.83 (dq, J=7.91, 7.66 Hz, 2H); 2.59(q, J=7.72 Hz, 4H); 3.31-3.45 (m, 2H); 3.52-3.63 (m, 2H); 3.81 (s, 3H);6.98 (d, J=8.67 Hz, 1H); 7.08-7.32 (m, 10H); 7.66 (d, J=2.26 Hz, 1H);7.74 (dd, J=8.48/2.26 Hz, 1H); 8.62 (s, 1H)

EXAMPLE 1702-[4-Acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid

The title compound was prepared according to the general proceduredescribed in example 125 using 0.3 g of resin (0.75 mmol/g).3-Hydroxy-4-iodo-benzoic acid was used in the acylation step. Finally,the resin with the iodo compound was reacted withtrimethylsilylacetylene (10 equivalents) dissolved in 4 ml of DMFtogether with triethylamine (20 equivalents), copper(I) iodide (0.1equivalents) and bis(triphenylphosphine)palladium(II) chloride (0.1equivalents) overnight at room temperature. The resin was washed withDMF and THF and treated with a 1 M solution of tetrabutylammoniumfluoride in THF for 30 min. After extensive washing with DCM, 10% aceticacid in DCM and DCM the compound was cleaved from the resin with neatTFA for 2 h. The carboxylic acid amide was converted into the carboxylicacid as described in the general procedure in example 125 and the titlecompound purified by preparative RP HPLC (water/ACN gradient). Yield:5.8 mg.

LC/MS (Method LC7): Rt=4.77 min; m/z=458.2 [MH⁺]

EXAMPLE 1712-[4-Methoxy-3-(2-m-tolyl-ethylamino)-benzoylamino]-indane-2-carboxylicacid

The title compound was prepared according to the general proceduredescribed in example 125 using 0.5 g of resin (0.75 mmol/g).4-Methoxy-3-nitro-benzoic acid in place of the hydroxy-substitutedbenzoic acid was used in the acylation step, and the nitro group wassubsequently reduced with a 1 M solution of tin(II) chloride dihydratein DMF overnight. The resin was washed with DMF, DCM and reacted with2,4-dinitro-benzenesulfonyl chloride (5 equivalents) and 2,6-lutidine(10 equivalents) dissolved in 5 ml of DCM for 5 h. After washing withDCM and THF, a solution of triphenylphosphine (10 equivalents) and2-(3-methylphenyl)-ethanol (10 equivalents) in THF was added to theresin and the slurry was cooled to 0° C. DIAD was added to the cooledmixture and the reaction mixture was shaken overnight at roomtemperature. The resin was washed with DCM and treated withmercaptoacetic acid (5 equivalents) and triethylamine (10 equivalents)in DCM for 10 min. The step was repeated with a fresh solution. Theresin was washed with DMF and DCM. The compound was cleaved from theresin with neat TFA for 2 h, the carboxylic acid amide was convertedinto the carboxylic acid as described in the general procedure inexample 125 and the title compound purified by preparative RP HPLC(water/ACN gradient). Yield: 36.4 mg.

LC/MS (Method LC7): Rt=3.80 min; m/z=445.2 [MH⁺]

¹H-NMR (300 MHz, D₆-DMSO+2% TFA): δ=2.27 (s, 3H); 2.83-2.92 (m, 2H);3.33-3.48 (m, 4H); 3.53-3.64 (m, 2H); 3.90 (s, 3H); 6.99-7.25 (m, 10H);7.56 (s, 1H); 7.63 (s, 1H); 8.72 (s, 1H)

EXAMPLE 1722-{4-Methoxy-3-[methyl-(2-m-tolyl-ethyl)-amino]-benzoylamino}-indane-2-carboxylicacid

First, the synthesis was carried out as described in example 171 using0.25 g of resin (0.75 mmol/g). Subsequently, for the N-methylation, theresin was treated with a 37% aqueous solution of formaldehyde (10equivalents) in DCM/ACN (3:1) containing 2% of acetic acid and 1.5 ml ofa 1 M sodium cyanoborohydride solution in THF overnight. The methylationreaction was repeated three times with fresh reagents. The cleavage,isolation and purification of the compound were performed as describedin example 171. Yield: 21.4 mg.

LC/MS (Method LC7): Rt=3.19 min; m/z=459.2 [MH⁺]

¹H-NMR (300 MHz, D₆-DMSO+2% TFA): δ=2.22 (s, 3H); 2.72 (t, J=7.82 Hz,2H); 3.23 (s, 3H); 3.34-3.45 (m, 2H); 3.63 (d, J=16.95 Hz, 2H); 3.78 (t,J=8.67 Hz, 2H); 3.99 (s, 3H); 6.89-6.96 (m, 2H); 7.00 (d, J=7.91 Hz,1H); 7.10-7.29 (m, 6H); 7.33 (d, J=8.85 Hz, 1H); 8.04 (dd, J=8.67/1.70Hz, 1H); 8.16 (s, 1H); 8.84 (s, 1H)

EXAMPLE 1732-[4-Cyano-3-(2-m-tolyl-ethylamino)-benzoylamino]-indane-2-carboxylicacid

0.1 g of PL Wang resin (Polymer Laboratories, Amherst, Mass., USA; 1.7mmol/g) was acylated with FMOC-protected 2-amino-indane-2-carboxylicacid (3 equivalents) in the presence of DIC (3 equivalents), HOBT (3equivalents) and 1-methylimidazole in DMF overnight. The FMOC protectinggroup was removed by treatment with 50 piperidine in DMF, and theobtained amino acid was acylated with 4-cyano-3-fluorobenzoic acid (3equivalents) in the presence of DIC (3 equivalents) and HOBT (3equivalents) in DMF. The resin was treated with a 1 M solution of2-(3-methyl-phenyl)-ethylamine in DMF overnight at room temperature. Thereaction was repeated with fresh amine solution. The resin was washedwith DMF and DCM and the compound was cleaved from the resin with neatTFA for 1.5 h. TFA was removed in vacuo and the compound was purified bypreparative RP HPLC (water/ACN gradient). Yield: 9.7 mg.

LC/MS (Method LC7): Rt=4.66 min; m/z=440.2 [MH⁺]

¹H-NMR (300 MHz, D₆-DMSO+2% TFA): δ=2.27 (s, 3H); 2.83 (t, J=7.44 Hz,2H); 3.33-3.47 (m, 4H); 3.54-3.65 (m, 2H); 6.98-7.11 (m, 4H); 7.11-7.26(m, 7H); 7.54 (d, J=8.10 Hz, 1H); 8.95 (s, 1H)

EXAMPLE 1742-[4-Cyano-3-[3-phenyl-pyrrolidin-1-yl)-benzoylamino]-indane-2-carboxylicacid

The synthesis was carried out as described in example 174 using 0.15 gof PL Wang resin (1.7 mmol/g). Instead of with2-(3-methyl-phenyl)-ethylamine, in the last step the resin was reactedwith 3-phenyl-pyrrolidine (8 equivalents) in dimethylacetamide at 90° C.overnight. The compound was cleaved, isolated and purified as describedin example 173.

Yield: 11.3 mg.

LC/MS (Method LC7): Rt=4.82 min; m/z=452.2 [MH⁺]

EXAMPLE 1752-{4-Cyano-3-[2-(2-fluoro-phenyl)-ethylamino]-benzoylamino}-indane-2-carboxylicacid

The synthesis was carried out as described in example 173 using 0.1 g ofPL Wang resin (1.7 mmol/g). Instead of with2-(3-methyl-phenyl)-ethylamine, in the last step the resin was reactedwith 2-(2-fluorophenyl)-ethylamine (10 equivalents) in dimethylacetamidein a microwave reactor at 150° C. for 1 h. The compound was cleaved,isolated and purified as described in example 173.

Yield: 1.7 mg.

LC/MS (Method LC7): Rt=4.51 min; m/z=444.2 [MH⁺]

EXAMPLE 1762-{3-[2-(3-Chloro-phenyl)-ethoxy]-4-methyl-benzoylamino}-indane-2-carboxylicacid

The synthesis was carried out on 0.15 g of PL Wang resin (1.7 mmol/g).The attachment of 2-amino-indane-2-carboxylic acid and the acylationwith 3-hydroxy-4-methylbenzoic acid were performed as in described inexample 173. After the acylation step, the resin was washed with THF anda solution of triphenylphosphine (10 equivalents) and2-(3-chlorophenyl)-ethanol (10 equivalents) in THF was added to theresin. The slurry was cooled to 0° C., DIAD (10 equivalents) was addedto the cooled mixture, and the reaction mixture was shaken overnight atroom temperature. The resin was washed with DCM. The compound wascleaved, isolated and purified as in described in example 173. Yield:2.3 mg.

LC/MS (Method LC7): Rt=5.11 min; m/z=450.2 [MH⁺]

EXAMPLE 1772-{3-[2-(2-Fluoro-phenyl)-ethoxy]-4-methyl-benzoylamino}-indane-2-carboxylicacid

The title compound was prepared as described in example 176. Yield: 3.8mg.

LC/MS (Method LC7): Rt=4.87 min; m/z=434.2 [MH⁺]

EXAMPLE 1782-[4-Ethoxy-3-(2-m-tolyl-ethylamino)-benzoylamino]-indane-2-carboxylicacid

The synthesis was carried out on 0.15 g of PL Wang resin (1.7 mmol/g).The attachment of 2-amino-indane-2-carboxylic acid and the acylationstep using 4-fluoro-3-nitro-benzoic acid were performed as described inexample 173. After the acylation step, the resin was shaken with ethanol(5 equivalents) in the presence of sodium bis(trimethylsilyl)amide (5equivalents) in 3 ml of dimethylacetamide. The resin was washed withDMF, 10% acetic acid/DMF, DMF and finally with DCM. The reduction of thenitro group with tin(II) chloride, sulfonylation with2,4-dinitro-benzenesulfonyl chloride, alkylation with2-(3-methylphenyl)-ethanol and removal of the sulfonyl group wereperformed as described in example 171 and the compound purified bypreparative RP HPLC (water/ACN gradient). Yield: 2.4 mg.

LC/MS (Method LC7): Rt=3.73 min; m/z=459.2 [MH⁺]

EXAMPLE 1792-[4-Hydroxy-3-(2-m-tolyl-ethylamino)-benzoylamino]-indane-2-carboxylicacid

10 mg of the compound of example 171 were dissolved in DCM and treatedwith 200 μl of a 1 M solution of boron tribromide in DCM for 5 h. A 2 Msolution of sodium carbonate was added, and the mixture was evaporatedin vacuo. The product was purified by preparative RP HPLC (water/ACNgradient).

LC/MS (Method LC7): Rt=3.34; m/z=431.2 [MH⁺]

¹H-NMR (300 MHz, D₆-DMSO+2% TFA): δ=2.21 (s, 3H); 2.81-2.92 (m, 2H);3.24-3.37 (m, 2H); 3.37-3.48 (m, 2H); 3.48-3.60 (m, 2H); 6.88-7.04 (m,5H); 7.04-7.21 (m, 6H); 7.66-7.79 (m, 2H); 8.66 (s, 1H)

EXAMPLE 1802-[4-Methoxy-3-(2-m-tolyl-ethylsulfanyl)-benzoylamino]-indane-2-carboxylicacid

Step 1 3-(5-Carboxy-2-methoxy-phenyldisulfanyl)-4-methoxy-benzoic acid

45 g (179.5 mmol) of 3-chlorosulfonyl-4-methoxy-benzoic acid weresuspended in 200 ml of acetic acid and warmed to 40° C. Then a solutionof 85.1 g (448.8 mmol) tin(II) chloride in 100 ml of hydrochloric acidwas added within 15 min and the mixture was stirred for 2 h underreflux. The hot solution was added dropwise to 2000 ml of ice/water. Theformed precipitate was collected by suction, washed with water anddried. 32.8 g of the title compound were obtained.

Step 2 4-Methoxy-3-(2-m-tolyl-ethylsulfanyl)-benzoic acid

732.8 mg (2 mmol) of the compound of step 1 were dissolved in 30 ml ofabsolute methanol and 151.3 mg (4 mmol) of sodium borohydride were addedslowly in portions. After stirring overnight, a solution of 796.4 mg (4mmol) of 1-(2-bromo-ethyl)-3-methyl-benzene in 10 ml of DCM was addedand the mixture was stirred overnight. Then 202.4 mg (4 mmol) oftriethylamine were added and stirring was continued for 2 h at roomtemperature and for 2 h at 40° C. After cooling, the mixture wasextracted with a sodium hydrogencarbonate solution and the organic phasewas dried and evaporated. The residue was used in the subsequent stepwithout further purification.

Step 32-[4-Methoxy-3-(2-m-tolyl-ethylsulfanyl)-benzoylamino]-indane-2-carboxylicacid

700 mg of the crude compound of step 2 were dissolved in 5 ml of DMF and598 mg (4.63 mmol) of EDIA and 968 mg (2.55 mmol) ofO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate were added. Then a solution of 527 mg (2.32 mmol) of2-amino-indane-2-carboxylic acid methyl ester hydrochloride in 5 ml ofDMF was added. After stirring overnight, EA and an aqueous solution oflithium chloride (4%) were added, the organic phase was separated,washed once with a solution of lithium chloride and twice with asolution of sodium hydrogencarbonate, dried and evaporated. The solidresidue was dissolved in 10 ml of a 9:1 mixture of THF and water, and131 mg (5.47 mmol) of lithium hydroxide were added. After stirringovernight, the mixture was evaporated to dryness. The residue waspurified by preparative RP HPLC (water/ACN gradient) to give 222 mg ofthe title compound.

LC/MS (Method LC3): Rt=1.97 min; m/z=462.23 [MH⁺]

¹H-NMR: δ=12.45 (br s, 1H); 8.87 (s, 1H); 7.78 (s, 1H); 7.74 (d, 1H);7.20-7.26 (m, 2H); 7.13-7.20 (m, 3H); 7.09 (s, 1H); 6.98-7.08 (m, 3H);3.87 (s, 3H); 3.60 (d, 2H); 3.18 (d, 2H); 2.82 (t, 2H); 2.29 (s, 3H)

EXAMPLE 1812-{3-[2-(3-Chloro-phenyl)-ethylsulfanyl]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

The title compound was obtained in analogy to example 180 by using1-(2-bromo-ethyl)-3-chloro-benzene instead of1-(2-bromo-ethyl)-3-methyl-benzene in step 2.

LC/MS (Method LC3): Rt=1.97 min; m/z=482.19 [MH⁺]

EXAMPLE 1822-(3-Benzylsulfanyl-4-methoxy-benzoylamino)-indane-2-carboxylic acid

The title compound was obtained in analogy to example 180 by usingbenzyl bromide instead of 1-(2-bromo-ethyl)-3-methyl-benzene in step 2.

LC/MS (Method LC3): Rt=1.80 min; m/z=434.26 [MH⁺]

EXAMPLE 1832-[4-Methoxy-3-(2-m-tolyl-ethanesulfonyl)-benzoylamino]-indane-2-carboxylicacid

55 mg (119.2 mmol) of the compound of example 180 were dissolved in 5 mlof DCM and treated with a solution of 88.2 mg (357.6 mmol) of3-chloroperbenzoic acid in 5 ml of DCM. After stirring at roomtemperature overnight, the solvent was evaporated and the residue waspurified by preparative RP HPLC (water/ACN gradient) to give 28 mg ofthe title compound.

LC/MS (Method LC3): Rt=1.68 min; m/z=494.25 [MH⁺]

¹H-NMR: δ=12.45 (br s, 1H); 9.00 (s, 1H); 8.30 (s, 1H); 7.21-7.28 (m,3H); 7.13-7.20 (m, 2H); 7.08 (t, 1H); 6.90-6.95 (m, 2H); 6.88 (s, 1H);3.94 (s, 3H); 3.70 (t, 2H); 3.60 (d, 2H); 3.42 (d, 2H); 2.82 (t, 2H);2.18 (s, 3H)

EXAMPLE 1842-{3-[2-(3-Chloro-phenyl)-ethanesulfonyl]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

The title compound was obtained in analogy to example 183, starting fromthe compound of example 181.

LC/MS (Method LC3): Rt=1.69 min; m/z=514.20 [MH⁺]

EXAMPLE 1852-[3-(2-m-Tolyl-ethoxy)-4-trifluoromethyl-benzoylamino]-indane-2-carboxylicacid

Step 1 3-Acetoxy-4-trifluoromethyl-benzoic acid

3.5 g (17 mmol) of 3-hydroxy-4-trifluoromethyl-benzoic acid (prepared asdescribed in WO 2006/128184) were dissolved in 35 ml of acetic acidanhydride and heated to reflux for 3 h. 60 ml of water were added andheating to reflux was continued for 10 min. After cooling and stirringovernight, the formed precipitate was collected by suction and dried togive 3.0 g of the title compound.

Step 2 2-(3-Acetoxy-4-trifluoromethyl-benzoylamino)-indane-2-carboxylicacid methyl ester

To a solution of 2.7 g (10.9 mmol) of the compound of step 1 in 16.3 mlof a 2 M solution of oxalyl chloride in DCM (32.6 mmol), 80 mg of DMFwere added and the mixture was stirred for 30 min at room temperature.The solvent was evaporated, 20 ml of DCM were added and the mixture wasevaporated again. The residue was dissolved in 20 ml of DCM and thesolution added within 5 min at 0° C. to a solution of 2.48 g (10.9 mmol)of 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in 50 mlof DCM and 30 ml of a saturated sodium hydrogencarbonate solution. Afterstirring overnight, the phases were separated, the organic phase wasdried over sodium sulfate, evaporated, and the residue was purified bysilica gel chromatography (HEP/EA gradient). 1.1 g of the title compoundwere obtained.

Step 32-[3-(2-m-Tolyl-ethoxy)-4-trifluoromethyl-benzoylamino]-indane-2-carboxylicacid methyl ester

200 mg (0.48 mmol) of the compound of step 2 were dissolved in 5 ml ofmethanol, 13.1 mg (0.1 mmol) of potassium carbonate were added and themixture was stirred for 30 min. The mixture was acidified with 1 Nhydrochloric acid and extracted three times with 20 ml portions of EA.The combined organic phases were dried and evaporated. The residue wasdissolved in 5 ml of THF, 96.9 mg (0.71 mmol) of2-(3-methylphenyl)-ethanol and 186.7 mg (0.71 mmol) oftriphenylphosphine were added, the mixture was cooled in an ice bath,and 191.9 mg (0.95 mmol) of DIAD were added. After stirring overnight,the mixture was evaporated to dryness and the residue was purified bypreparative RP HPLC (water/ACN gradient). 104 mg of the title compoundwere obtained.

Step 42-[3-(2-m-Tolyl-ethoxy)-4-trifluoromethyl-benzoylamino]-indane-2-carboxylicacid

The title compound was obtained from the compound of step 3 byhydrolysis with lithium hydroxide in analogy to example 180, step 3.

LC/MS (Method LC3): Rt=2.15 min; m/z=484.19 [MH⁺]

¹H-NMR: δ=12.50 (br s, 1H); 9.00 (s, 1H); 7.69 (d, 1H); 7.59 (s, 1H);7.55 (d, 1H); 7.20-7.26 (m, 2H); 7.13-7.20 (m, 4H); 7.11 (d, 1H); 7.03(d, 1H); 4.35 (t, 2H); 3.60 (d, 2H); 3.39 (d, 2H); 3.02 (t, 2H); 2.29(s, 3H)

In analogy to example 185, the example compounds of the formula Itlisted in table 6 were prepared by using the respective 2-(substitutedphenyl)-ethanol instead of 2-(3-methylphenyl)-ethanol in step 3. Thecompounds can be named as2-{3-[2-(R⁹⁶)-ethoxy]-4-trifluoromethyl-benzoylamino}-indane-2-carboxylicacid, for example as2-{3-[2-(3-chloro-phenyl)-ethoxy]-4-trifluoromethyl-benzoylamino}-indane-2-carboxylicacid in the case of example 186.

TABLE 6 Example compounds of the formula It LC/MS m/z Retention ExampleR⁹⁶ Method [MH⁺] time [min] 186 3-chloro-phenyl LC3 504.24 2.15 1872-chloro-6-fluoro-phenyl LC3 522.04 2.10 188 2,5-difluoro-phenyl LC3506.07 2.03 189 5-chloro-2-fluoro-phenyl LC3 522.06 2.12 1903-methyl-pyrazin-2-yl LC3 486.23 1.67 191 2-fluoro-5-trifluoromethyl-LC3 556.26 2.14 phenyl 192 2-fluoro-5-methyl-phenyl LC4 502.17 2.67

EXAMPLE 1932-{3-[2-(5-Chloro-2-fluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

Step 1 2-(5-Chloro-2-fluoro-phenyl)-ethanol

A solution of 5 g (26.51 mmol) of 5-chloro-2-fluoro-phenylacetic acid in60 ml of THF was added dropped to a suspension of 2.012 g (53.02 mmol)of lithium aluminium hydride in 26.5 ml of THF. 30 ml of THF were added,and the mixture was heated under reflux for 3 h. After cooling to 0° C.,a solution of 929.7 mg (16.57 mmol) of potassium hydroxide in 4 ml ofwater was cautiously added and the mixture was stirred overnight at roomtemperature. The formed precipitate was filtered off with suction andwashed with THF. The combined filtrates were dried over sodium sulfate,filtered and evaporated to dryness. The residue was purified by silicagel chromatography (DCM/methanol 98:2) to give 3.8 g of the titlecompound.

Step 22-{3-[2-(5-Chloro-2-fluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

The title compound was obtained in analogy to example 185 by using in2-(5-chloro-2-fluoro-phenyl)-ethanol instead of2-(3-methylphenyl)-ethanol in step 3.

LC/MS (Method LC4): Rt=2.35 min; m/z=484.13 [MH⁺]

¹H-NMR: δ=12.45 (br s, 1H); 8.61 (s, 1H); 7.55 (m, 1H) 7.50 (d, 1H);7.45 (s, 1H); 7.30-7.37 (m, 1H); 7.18-7.26 (m, 3H); 7.11-7.19 (m, 2H);7.00 (d, 1H); 4.21 (t, 2H); 3.80 (s, 3H); 3.59 (d, 2H); 3.35 (d, 2H);3.06 (t, 2H)

EXAMPLE 1942-[4-Methoxy-3-(4-trifluoromethyl-phenylethynyl)-benzoylamino]-indane-2-carboxylicacid

Step 1 2-(3-Bromo-4-methoxy-benzoylamino)-indane-2-carboxylic acidmethyl ester

3-Bromo-4-methoxybenzoic acid (22.8 g, 98.8 mmol) was dissolved inthionyl chloride (42 ml) and stirred at 60° C. for 30 min. The volatileswere evaporated in vacuo and the residue was stripped with dioxane. Theobtained acid chloride was dissolved in DCM (50 ml).2-Amino-indane-2-carboxylic acid methyl ester hydrochloride (15.0 g,65.9 mmol) was suspended in DCM (100 ml), EDIA (10.2 g, 79.1 mmol) wasadded, the mixture was cooled in an ice bath, and the solution of theacid chloride was slowly added. The mixture was stirred overnight atroom temperature and evaporated to dryness. The residue was purified bysilica gel chromatography (DCM/methanol gradient) and subsequentcrystallization from EA to give 21.8 g of the title compound.

LC/MS (Method LC3): Rt=1.495 min; m/z=404.0/406.0 [MH⁺]

Step 22-[4-Methoxy-3-(4-trifluoromethyl-phenylethynyl)-benzoylamino]-indane-2-carboxylicacid methyl ester

300 mg (0.74 mmol) of the compound of step 1 and 90.1 mg (0.89 mmol) oftriethylamine were dissolved in 10 ml of dry toluene. 171.5 mg (148μmol) of tetrakis(triphenylphosphine)palladium(0) and 14.1 mg (74 μmol)of copper(I) iodide were added, and the mixture was stirred for 30 min.Subsequently 126.2 mg (0.74 mmol) of 1-ethynyl-4-trifluoromethyl-benzenewere added and the mixture was heated to 100° C. for 10 h. The mixturewas filtered, the solvent was evaporated and the residue was purified bypreparative RP HPLC (water/ACN gradient) to give 40 mg of the titlecompound.

Step 32-[4-Methoxy-3-(4-trifluoromethyl-phenylethynyl)-benzoylamino]-indane-2-carboxylicacid

From the compound of step 2, the title compound was obtained byhydrolysis with lithium hydroxide in analogy to example 180, step 3, andpurification by silica gel chromatography (DCM/methanol 98:2). Yield: 32mg.

LC/MS (Method LC4): Rt=2.57 min; m/z=480.17 [MH⁺]

¹H-NMR: δ=12.45 (br s, 1H); 8.80 (s, 1H); 8.09 (s, 1H); 7.94 (d, 1H);7.80 (d, 2H); 7.74 (d, 2H); 7.60-7.65 (m, 1H); 7.13-7.25 (m, 4H); 3.91(s, 3H); 3.57 (d, 2H); 3.40 (d, 2H)

EXAMPLE 1952-[3-(4-tert-Butyl-phenylethynyl)-4-methoxy-benzoylamino]-indane-2-carboxylicacid

The title compound was obtained in analogy to example 194 by using1-tert-butyl-4-ethynyl-benzene instead of1-ethynyl-4-trifluoromethyl-benzene.

LC/MS (Method LC4): Rt=2.79 min; m/z=486.24 [MH⁺]

EXAMPLE 1962-[(3′-Isopropyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylicacid

250 mg (0.62 mmol) of the compound of example 194, step 1, and 152.1 mg(0.93 mmol) of 3-isopropylphenylboronic acid were dissolved in 5 ml ofDMF and 5 ml of toluene under an argon atmosphere. 187.9 mg (1.24 mmol)of cesium fluoride and 35.73 mg (0.05 mmol) oftetrakis(triphenylphosphine)palladium(0) were added, and the mixture wasstirred overnight at 100° C. After cooling, the mixture was filtered andthe solvent was evaporated. The obtained2-[(3′-isopropyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylicacid methyl ester was dissolved in 10 ml of a mixture of THF and water(9:1), 42.2 mg (1.80 mmol) of lithium hydroxide were added and themixture was stirred overnight. The solvent was evaporated and theresidue was purified by preparative RP HPLC (water/ACN gradient). 71 mgof the title compound were obtained.

LC/MS (Method LC4): Rt=2.50 min; m/z=430.30 [MH⁺]

¹H-NMR: δ=12.5 (br s, 1H); 8.72 (s, 1H); 7.89 (d, 1H); 7.80 (s, 1H);7.13-7.37 (m, 9H); 3.81 (s, 3H); 3.60 (d, 2H); 2.92 (m, 1H); 1.24 (d,6H)

In analogy to example 196, the example compounds of the formula Iulisted in table 7 were prepared by using the respective substitutedphenylboronic acid instead of 3-isopropylphenylboronic acid. In the caseof examples 198 and 199, the intermediary 2-[(substitutedbiphenyl-3-carbonyl)-amino]-indane-2-carboxylic acid methyl ester waspurified by preparative RP HPLC (water/ACN gradient) before hydrolysis.The compounds can be named as 2-[(substitutedbiphenyl-3-carbonyl)-amino]-indane-2-carboxylic acid, for example as2-[(3′-cyanomethyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylicacid in the case of example 199 in which the group R⁹⁷ is3-cyanomethyl-phenyl and, in view of the rules of nomenclature, thegroup 3-(R⁹⁷)-4-methoxy-phenyl-C(O) depicted in formula Iu thus is named3′-cyanomethyl-6-methoxy-biphenyl-3-carbonyl.

TABLE 7 Example compounds of the formula Iu LC/MS m/z Retention ExampleR⁹⁷ Method [MH⁺] time [min] 197 4-isobutyl-phenyl LC4 444.32 2.70 1983-chloro-phenyl LC4 422.22 2.32 199 3-cyanomethyl-phenyl LC4 427.27 1.99200 3-trifluoromethyl-phenyl LC4 456.24 2.38 201 4-tert-butyl-phenyl LC4444.32 2.63 202 3-ethyl-phenyl LC3 416.32 1.95 2033-dimethylaminosulfonyl-  LC10 510.22 2.30 amino-phenyl

EXAMPLE 2042-{3-[2-(2,5-Difluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

Step 12-{3-[2-(2,5-Difluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid methyl ester

300.1 mg (0.88 mmol) of2-(3-hydroxy-4-methoxy-benzoylamino)-indane-2-carboxylic acid methylester, 208.6 mg (1.32 mmol) of 2-(2,5-difluoro-phenyl)-ethanol and 346mg (1.32 mmol) of triphenylphosphine were dissolved in 10 ml of THF. Themixture was cooled in an ice bath, and 355.5 mg (1.76 mmol) of DIAD wereadded. After stirring overnight, the mixture was evaporated to drynessand the residue was purified by preparative RP HPLC (water/ACNgradient). 340 mg of the title compound were obtained.

Step 22-{3-[2-(2,5-Difluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

From the compound of step 1, the title compound was obtained byhydrolysis with lithium hydroxide in analogy to example 180, step 3, andpurification by preparative

RP HPLC (water/ACN gradient). Yield: 260 mg.

LC/MS (Method LC3): Rt=1.81 min; m/z=468.11 [MH⁺]

¹H-NMR: δ=12.5 (br s, 1H); 8.63 (s, 1H); 7.51 (d, 1H); 7.44 (s, 1H);7.30-7.10 (m, 6H); 7.00 (d, 1H); 4.22 (t, 2H); 3.79 (s, 3H); 3.59 (d,2H); 3.38 (d, 2H); 3.08 (t, 2H)

EXAMPLE 2052-{3-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

The title compound was obtained in analogy to example 204 by using2-(5-ethyl-pyridin-2-yl)-ethanol instead 2-(2,5-difluoro-phenyl)-ethanolin step 1.

LC/MS (Method LC3): Rt=1.22 min; m/z=461.34 [MH⁺]

EXAMPLE 2062-{4-Methoxy-3-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzoylamino}-indane-2-carboxylicacid

The title compound was obtained in analogy to example 204 using2-(4-methyl-thiazol-5-yl)-ethanol instead2-(2,5-difluoro-phenyl)-ethanol in step 1.

LC/MS (Method LC4): Rt=2.70 min; m/z=453.11 [MH⁺]

EXAMPLE 2076-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-6,7-dihydro-5H-cyclopentapyrazine-6-carboxylicacid

The title compound was obtained from 2,3-bis-chloromethyl-pyrazine (K.Yoshiizumi et al., Bioorg. Med. Chem. 11 (2003), 433-450) in analogy toexamples 97 and 98, using N-methylpyrrolidone instead of DMF as solventin the initial cyclization step.

The intermediary amino acid ester was not purified, but used as rawmaterial. LC/MS (Method LC1): Rt=1.32 min; m/z=448.0 [MH⁺]

EXAMPLE 2082-{[6-Methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-indane-2-carboxylicacid

6-Chloro-5-nitro-nicotinic acid methyl ester was prepared according tothe procedure described in WO 2005/021544 and transformed into5-hydroxy-6-methoxy-nicotinic acid methyl ester according to theprocedure described in WO 95/04045, which was then transformed into thetitle compound by etherification with 2-m-tolyl-ethanol in analogy tostep 1 of example 1, hydrolysis of the ester group in analogy to example2, reaction of the obtained carboxylic acid with2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogyto step 1 of example 15, and hydrolysis of the ester group in analogy toexample 2.

¹H-NMR: δ=12.5 (s, 1H); 8.75 (s, 1H); 8.21 (d, 1H); 7.63 (d, 1H);7.75-7.13 (m, 6H); 7.11 (d, 1H); 7.02 (d, 1H); 4.21 (t, 2H); 3.91 (s,3H); 3.61 (d, 2H); 3.37 (d, 2H); 3.01 (t, 2H); 2.28 (s, 3H)

EXAMPLE 2092-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-1-methyl-indane-2-carboxylicacid

Step 1 1-(1-Chloro-ethyl)-2-chloromethyl-benzene

1-(2-Hydroxymethyl-phenyl)-ethanol (prepared according to the proceduredescribed in P. Canorme et al., Tetrahedron 44 (1988), 2903-2912) (0.376g, 2.47 mmol) was dissolved in DCM. Thionyl chloride (2.94 g, 24 mmol)was added and allowed to react for 1 h. The mixture was partitionedbetween EA and an excess of an aqueous sodium hydrogencarbonatesolution. The combined organic extracts were dried over sodium sulfate,filtered and evaporated to dryness in vacuo. The residue was purified bysilica gel chromatography with HEP to yield 0.228 g of the titlecompound.

¹H-NMR: δ=7.68 (dd, 1H); 7.46-7.41 (m, 2H); 7.35 (dd, 1H); 5.66 (q, 1H);4.95 (d, 1H); 4.90 (d, 1H); 1.82 (d, 3H)

Step 22-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-1-methyl-indane-2-carboxylicacid

The title compound was obtained from the compound of step 1 in analogyto examples 97 and 98, using N-methylpyrrolidone instead of DMF assolvent in the initial cyclization step. The intermediary amino acidester was not purified, but used as raw material.

LC/MS (Method LC1): Rt=1.66 min; m/z=460.2 [MH⁺]

EXAMPLE 2102-(3-{2-[3-(2-Hydroxy-1-hydroxymethyl-1-methyl-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylicacid

Step 1 2-(3-Methoxycarbonylmethyl-phenyl)-malonic acid dimethyl ester

Tris(dibenzylideneacetone)dipalladium(0) (0.104 g, 0.113 mmol),tri-(tert-butyl)phosphonium tetrafluoroborate (65.8 mg, 0.227 mmol) andsodium hydride (295 mg, 60% dispersion in mineral oil) were charged intoa flask under an argon atmosphere. (3-Bromophenyl)acetic acid methylester (1.30 g, 5.67 mmol) was dissolved in THF (10 ml) and added to themixture. Subsequently, dimethyl malonate (0.995 g, 7.37 mmol) was addedand the mixture stirred under reflux overnight. The mixture was filteredover a small plug of silica gel, evaporated to dryness and the residuepurified by silica gel chromatography (HEP/EA gradient) to yield 0.704 gof the title compound.

LC/MS (Method LC1): Rt=1.28 min; m/z=281.1 [MH⁺]

Step 2 2-(3-Methoxycarbonylmethyl-phenyl)-2-methyl-malonic acid dimethylester

The compound of step 1 (0.353 g, 1.26 mmol) was dissolved in DMF (1.5ml), potassium tert-butoxide (151 mg, 1.32 mmol) was added, the mixturestirred at room temperature for 10 min, and then iodomethane (0.542 g,3.78 mmol) was added. The mixture was stirred at room temperature for 3h and partitioned between EA and 2 N hydrochloric acid. The combinedextracts were washed with a saturated aqueous sodium chloride solution,dried over sodium sulfate and evaporated to dryness. The residue waspurified by preparative RP HPLC (water/ACN gradient) to yield 0.128 g ofthe title compound.

LC/MS (Method LC1): Rt=1.36 min; m/z=295.0 [MH⁺]

Step 3 2-[3-(2-Hydroxy-ethyl)-phenyl]-2-methyl-propane-1,3-diol

The compound of step 2 (0.128 g, 0.435 mmol) was dissolved in 2 ml ofTHF and cautiously added to an ice-cold suspension of lithium aluminiumhydride (174 mg, 4.35 mmol) in THF. After a few minutes, diethyl ether(12 ml) was added and thereafter 200 μl of EA. Subsequently, water wasadded slowly and cautiously until the alumina salts formed a light greymass at the bottom of the flask. The supernatant was decanted and theresidue washed with EA. The combined extracts were dried over sodiumsulfate and evaporated to dryness. The residue was used in the next stepwithout further purification.

LC/MS (Method LC1): Rt=0.69 min; m/z=228.1 [MNH₄ ⁺]

Step 42-(3-{2-[3-(2-Hydroxy-1-hydroxymethyl-1-methyl-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylicacid

The compound of step 3 was reacted with methyl3-hydroxy-4-methoxybenzoate in analogy to step 1 of example 94. From theobtained intermediate the title compound was prepared in analogy to step1 of example 15.

LC/MS (Method LC1): Rt=1.28 min; m/z=520.1 [MH⁺]

EXAMPLE 2112-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-octahydro-indene-2-carboxylicacid

Acetyl chloride (22 mg, 0.282 mmol) was cautiously dissolved in ethanol(2 ml). 2-Amino-indane-2-carboxylic acid (50 mg, 0.282 mmol) andplatinum dioxide (25 mg) were added, and the mixture was hydrogenated atroom temperature at a hydrogen pressure of 5 bar for 5 h. The solutionwas filtered over a small plug of celite and evaporated to dryness. Forconversion into 2-amino-octahydroindene-2-carboxylic acid methyl ester,the residue was suspended in methanol (2 ml), thionyl chloride (0.5 ml)was added and the mixture was stirred overnight at room temperature. Themixture was evaporated to dryness to yield 99 mg of raw material whichwas used in the next step without further purification. From theobtained intermediate, the title compound was prepared in analogy tostep 1 of example 15 and hydrolysis of the ester group in analogy toexample 2.

¹H-NMR: δ=12.0 (s, 1H); 8.40 (s, 1H); 7.48 (dd, 1H); 7.41 (dd, 1H);7.22-7.16 (m, 2H); 7.11 (d, 1H); 7.04 (d, 1H); 7.00 (d, 1H); 4.18 (t,2H); 3.80 (s, 3H); 3.01 (t, 2H); 2.29 (s, 3H); 2.20-2.00 (m, 6H);1.53-1.40 (m, 6H); 1.32-1.20 (m, 2H)

EXAMPLE 2122-{3-[2-(3-Chloro-phenyl)-2,2-difluoro-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

Step 1 2-(3-Chloro-phenyl)-2,2-difluoro-ethanol

1.00 g (4.26 mmol) (3-chloro-phenyl)-difluoro-acetic acid ethyl ester(prepared according to the procedure described in WO 2006/122788) weredissolved in 100 ml of methanol and treated in an ice bath with 120 mg(0.75 mmol) of sodium borohydride. After stirring overnight the mixturewas evaporated and the residue was purified by silica gel chromatography(DCM/methanol 98:2) to give 700 mg of the title compound.

Step 2 Trifluoromethanesulfonic acid2-(3-chloro-phenyl)-2,2-difluoro-ethyl ester

700 mg (3.64 mmol) of the compound of step 1 were dissolved in 10 ml ofDCM and treated at 0° C. with 78 μl (4.36 mmol) of EDIA and 1.23 g (4.36mmol) of trifluoromethanesulfonic acid anhydride. After completion ofthe reaction (monitored by thin layer chromatography (DCM/methanol98:2), the mixture was poured on water and the phases were separated.The organic phase was washed once with a saturated sodium chloridesolution, dried over sodium sulfate and evaporated to dryness. Theresidue was purified by silica gel chromatography (DCM) to give 450 mgof the title compound.

Step 32-{3-[2-(3-Chloro-phenyl)-2,2-difluoro-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid methyl ester

To a mixture of 230 mg (0.67 mmol) of2-(3-hydroxy-4-methoxy-benzoylamino)-indane-2-carboxylic acid methylester and 227 mg (1.62 mmol) of potassium carbonate in 6 ml of acetoneand 1.7 ml of DMF was added slowly a solution of 437 mg (1.65 mmol) ofthe compound of step 2. The reaction mixture was stirred for 3 d at roomtemperature and then evaporated. The residue was purified by preparativeRP HPLC (water/ACN gradient) to give 20 mg of the title compound.

Step 42-{3-[2-(3-Chloro-phenyl)-2,2-difluoro-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

20 mg of the compound of step 3 were dissolved in 5 ml of a mixture ofTHF and water (9:1), and 1.9 mg (77.5 μmol) of lithium hydroxide wereadded. After stirring at room temperature for 3 d, the mixture wasacidified with 1 M hydrochloric acid and evaporated. The residue waspurified by silica gel chromatography (DCM/methanol 95:5) and RP HPLC(water/ACN gradient) to give 8 mg of the title compound.

LC/MS (Method LC1): Rt=1.64 min; m/z=502.10 [MH⁺]

¹H-NMR: δ=12.45 (br s, 1H); 8.62 (s, 1H); 7.75 (s, 1H); 7.50-7.65 (m,4H); 7.48 (s, 1H); 7.23 (m, 2H) 7.17 (m, 2H); 7.04 (d, 1H); 4.65 (t,2H); 3.80 (s, 3H); 3.59 (d, 2H); 3.38 (d, 2H)

EXAMPLE 2132-[3-(2,2-Difluoro-2-phenyl-ethoxy)-4-methoxy-benzoylamino]-indane-2-carboxylicacid

The title compound was obtained in analogy to example 212, starting from2,2-difluoro-2-phenyl-ethanol.

LC/MS (Method LC1): Rt=1.53 min; m/z=468.15 [MH⁺]

¹H-NMR: δ=12.45 (br s, 1H); 8.62 (s, 1H); 7.64 (d, 2H); 7.46-7.59 (m,5H); 7.22 (m, 2H) 7.17 (m, 2H); 7.04 (d, 1H); 4.60 (t, 2H); 3.80 (s,3H); 3.58 (d, 2H); 3.38 (d, 2H)

EXAMPLE 2144,7-Difluoro-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

Step 1 (3,6-Difluoro-2-hydroxymethyl-phenyl)-methanol

Lithium aluminium hydride (792 mg, 19.8 mmol) was suspended in THF (6ml) and cooled in an ice bath. A solution of4,7-difluoro-isobenzofuran-1,3-dione (730 mg, 3.97 mmol) in THF (6 ml)was added during 5 min. After completion of the reaction (5 min),diethyl ether (30 ml) was added. Subsequently, 2 ml of EA were added inorder to decompose excess of lithium aluminium hydride, and thereafterwater was slowly added until the alumina salts precipitated. Thesupernatant was decanted and the precipitate washed twice with EA. Thecombined extracts were dried over sodium sulfate, filtered andevaporated to dryness to yield 360 mg of the title compound.

¹H-NMR: δ=7.16 (t, 2H); 5.13 (t, 2H); 4.60 (d, 4H)

Step 2 2,3-Bis-chloromethyl-1,4-difluoro-benzene

The compound of step 1 (360 mg, 2.07 mmol) was dissolved in acetylchloride (2.3 ml) in a vial. After 10 min, zinc chloride (843 mg, 6.21mmol) was added and the mixture was heated to 130° C. in a microwavereactor for 30 min. After cooling, the mixture was partitioned betweendiethyl ether and saturated sodium hydrogencarbonate solution and theaqueous phase extracted with diethyl ether. The combined organic phaseswere dried over sodium sulfate, filtered and evaporated to dryness toyield 200 mg of the title compound.

¹H-NMR: δ=7.40 (t, 2H); 4.90 (s, 4H)

Step 34,7-Difluoro-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The compound of step 2 was transformed into the title compound inanalogy to examples 97 and 98.

LC/MS (Method LC13): Rt=2.60 min; m/z=482.2 [MH⁺]

EXAMPLE 2154-Fluoro-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The title compound was prepared in analogy to example 214, starting from(3-fluoro-2-hydroxymethyl-phenyl)-methanol.

LC/MS (Method LC11): Rt=1.91 min; m/z=464.2 [MH⁺]

EXAMPLE 2162-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl-indane-2-carboxylicacid

The title compound was prepared in analogy to example 214, starting from4-methyl-isobenzofuran-1,3-dione.

LC/MS (Method LC12): Rt=3.74 min; m/z=460.2 [MH⁺]

EXAMPLE 2174-Chloro-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The title compound was prepared in analogy to example 214, starting from4-chloro-isobenzofuran-1,3-dione.

LC/MS (Method LC13): Rt=2.67 min; m/z=480.2 [MH⁺]

EXAMPLE 2185-Cyano-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

Step 15-Bromo-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid ethyl ester

Starting from 5-bromo-3H-isobenzofuran-1-one, the intermediate4-bromo-1,2-bis-chloromethyl-benzene was prepared in analogy to steps 1and 2 of example 214.

This intermediate was transformed into the title compound in analogy toexample 97. LC/MS (Method LC13): Rt=3.03 min; m/z=552.2 [MH⁺]

Step 25-Cyano-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid ethyl ester

The compound of step 1 (50 mg, 0.091 mmol) was added to a mixture ofzinc cyanide (10.6 mg, 0.091 mmol) andtetrakis(triphenylphosphine)palladium(0) (5.2 mg, 0.004 mmol) in DMF(0.16 ml) at 150° C. and stirred for 2 h. After cooling, tert-butylmethyl ether was added and the mixture was filtered over celite. Thefiltrate was washed with water, the organic phase dried over magnesiumsulfate, filtered and evaporated to dryness to yield the title compoundwhich was used without further purification.

Step 35-Cyano-2-[4-methyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The compound of step 2 was transformed into the title compound byhydrolysis in analogy to step 3 of example 94.

LC/MS (Method LC13): Rt=2.54 min; m/z=471.3 [MH⁺]

EXAMPLE 2195-Carbamoyl-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The compound of step 2 of example 218 was transformed into the titlecompound by hydrolysis in analogy to example 98 (hydrolysis time 3 h).

LC/MS (Method LC14): Rt=3.68 min; m/z=489.3 [MH⁺]

EXAMPLE 2201-Hydroxy-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

Step 12-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-1-oxo-indane-2-carboxylicacid ethyl ester

2-Amino-1-oxo-indane-2-carboxylic acid ethyl ester (L. Benati et al., J.Org. Chem. 64 (1999), 7836-7841) (460 mg, 2.10 mmol) was reacted with4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 2 ofexample 13 to yield 0.331 g of the title compound.

LC/MS (Method LC12): Rt=4.09 min; m/z=488.2 [MH⁺]

Step 21-Hydroxy-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid ethyl ester

The compound of step 1 (0.439 g, 0.900 mmol) was dissolved in THF (4ml). The mixture was cooled to −30° C. and sodium borohydride (35 mg,0.90 mmol) was added followed by dropwise addition of methanol. After 30min, the mixture was partitioned between diethyl ether and 2 Nhydrochloric acid, the aqueous phase was extracted with diethyl ether,the combined organic phases were dried over sodium sulfate andevaporated to dryness. The residue was purified by silica gelchromatography (HEP/EA gradient) to yield the title compound as amixture of stereoisomers.

LC/MS (Method LC12): Rt=3.77 min; m/z=490.3 [MH⁺]

Step 31-Hydroxy-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The compound of step 2 was hydrolyzed in analogy to example 2.Purification by RP HPLC (water/ACN gradient) gave one of thediastereomers (diastereomer A) of the title compound in pure form (asthe racemate) and a mixture of the other diastereomer with diastereomerA (relative stereochemistry of the diastereomers unknown).

Diastereomer A:

LC/MS (Method LC12): Rt=3.43 min; m/z=462.2 [MH⁺]

¹H-NMR: δ=12.1 (br s, 1H); 8.43 (s, 1H); 7.48 (dd, 1H); 7.41 (d, 1H);7.32 (dd, 1H); 7.28-7.13 (m, 5H); 7.10 (d, 1H); 7.02 (d, 1H); 7.00 (d,1H); 5.70 (br s, 1H); 5.40 (s, 1H); 4.16 (t, 2H); 3.90 (d, 1H); 3.09 (d,1H); 3.00 (t, 2H); 2.28 (s, 3H)

EXAMPLE 2212-{[5-(3-Isopropyl-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-indane-2-carboxylicacid

Step 1 5-(3-Isopropyl-phenyl)-6-methoxy-nicotinic acid methyl ester

Under an atmosphere of argon, a mixture of 5-bromo-6-methoxy-nicotinicacid methyl ester (W. J. Thompson and J. Gaudino, J. Org. Chem. 49(1984), 5237-5243) (100 mg, 0.406 mmol), 3-isopropylphenylboronic acid(73 mg, 0.447 mmol), tri-(tert-butyl)phosphonium tetrafluoroborate (7mg, 0.024 mmol), tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.012mmol) and potassium fluoride (78 mg, 1.34 mmol) in a flask was suspendedin dioxane (1.5 ml) and heated to 45° C. for 3 h. After cooling, it wasfiltered over a small plug of silica gel and evaporated to dryness.Purification of the residue by silica gel chromatography (HEP/EAgradient) and subsequent RP HPLC (water/ACN gradient) yielded 63 mg ofthe title compound.

LC/MS (Method LC13): Rt=2.95 min; m/z=286.1 [MH⁺]

Step 2 5-(3-Isopropyl-phenyl)-6-methoxy-nicotinic acid

The compound of step 1 (60 mg, 0.63 mmol) was hydrolyzed in analogy tostep 3 of example 94 to yield 57 mg of the title compound.

LC/MS (Method LC13): Rt=2.48 min; m/z=272.1 [MH⁺]

Step 32-{[5-(3-Isopropyl-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-indane-2-carboxylicacid

The compound of step 2 was reacted with 2-amino-indane-2-carboxylic acidmethyl ester hydrochloride in analogy to step 2 of example 13, and theobtained ester hydrolyzed in analogy to example 2.

LC/MS (Method LC14): Rt=3.52 min; m/z=431.2 [MH⁺]

EXAMPLE 2222-{[6-Methoxy-5-(3-methylsulfanyl-phenyl)-pyridine-3-carbonyl]-amino}-indane-2-carboxylicacid

Step 12-[(5-Bromo-6-methoxy-pyridine-3-carbonyl)-amino]-indane-2-carboxylicacid methyl ester

5-Bromo-6-methoxy-nicotinic acid methyl ester (W. J. Thompson and J.Gaudino, J. Org. Chem. 49 (1984), 5237-5243) (2.00 g, 8.13 mmol) washydrolyzed in analogy to example 2. The obtained acid was reacted with2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogyto step 2 of example 13.

LC/MS (Method LC14): Rt=3.28 min; m/z=405.0 [MH^(+])

Step 22-{[6-Methoxy-5-(3-methylsulfanyl-phenyl)-pyridine-3-carbonyl]-amino}-indane-2-carboxylicacid

The compound of step 1 was reacted with 3-methylsulfanyl-phenylboronicacid in analogy to step 1 of example 221. The intermediate ester washydrolyzed in analogy to example 2.

LC/MS (Method LC14): Rt=3.30 min; m/z=435.1 [MH⁺]

In analogy to example 221 and example 222, respectively, the examplecompounds of the formula Iv listed in table 8 were prepared by using therespective substituted phenylboronic acid. If the initial palladiumcoupling reaction in the preparation analogously to example 221 did notproceed satisfactorily, it was repeated once more. The compounds can benamed as 2-{[5-(substitutedphenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-indane-2-carboxylic acid,for example as2-{[6-methoxy-5-(3-methyl-phenyl)-pyridine-3-carbonyl]-amino}-indane-2-carboxylicacid in the case of example 224.

TABLE 8 Example compounds of the formula Iv LC/MS m/z Retention ExampleR⁹⁸ Preparation Method [MH⁺] time [min] 223 3-chloro-phenyl (a) LC14423.1 3.00 224 3-methyl-phenyl (a) LC12 403.1 3.57 225 2-chloro-phenyl(a) LC12 423.0 3.49 226 4-chloro-phenyl (a) LC17 423.3 4.79 2272-chloro-3-trifluoromethyl-phenyl (a) LC14 457.1 3.43 2282,3-dichloro-phenyl (a) LC12 457.1 3.65 229 3,4,5-trifluoro-phenyl (b)LC12 443.2 3.68 230 2-fluoro-3-trifluoromethyl-phenyl (b) LC14 475.13.46 231 3-dimethylaminosulfonylamino- (b) LC14 511.2 2.94 phenyl 2323-chloro-4-trifluoromethyl-phenyl (b) LC16 978.9(c) 4.99 2333-ethylsulfanyl-phenyl (b) LC12 449.2 3.70 234 3-trifluoromethoxy-phenyl(b) LC17 473.2 4.89 235 3-chloro-5-trifluoromethyl-phenyl (b) LC14 491.23.71 236 3-cyano-phenyl (b) LC12 414.2 3.30 (a) preparation in analogyto example 221 (b) preparation in analogy to example 222 (c) [(2M − H)⁻]instead of [MH⁺]

EXAMPLE 2372-{[5-(3-Ethanesulfonyl-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-indane-2-carboxylicacid

The compound of example 233 (50 mg, 0.11 mmol) was dissolved in aceticacid (3.8 ml). Hydrogen peroxide (30% solution in water, 0.034 ml, 0.33mmol) was added and the mixture was reacted at room temperature for 72h. The mixture was partitioned between EA and an aqueous solution ofsodium sulfite (about 1 strength). The organic phase was dried overmagnesium sulfate, filtered and evaporated to dryness. The residue waspurified by RP HPLC (water/ACN gradient). After evaporation of theproduct fraction, the residue was stirred with a mixture of diethylether/HEP, filtered and dried in vacuo.

LC/MS (Method LC14): Rt=3.88 min; m/z=481.2 [MH⁺]

EXAMPLE 238 2-(4-Methoxy-3-o-tolyloxy-benzoylamino)-indane-2-carboxylicacid

Step 1 4-Methoxy-3-o-tolyloxy-benzoic acid

Potassium carbonate (1.20 g, 8.66 mmol), o-cresol (468 mg, 4.33 mmol),copper powder (28 mg, 0.43 mmol) and 3-bromo-4-methoxybenzoic acid (1.00g, 4.33 mmol) were suspended in DMF (5 ml) and heated to 165° C.overnight. Potassium carbonate (1.20 g, 8.66 mmol) and o-cresol (468 mg,4.33 mmol) were added once again and heating was continued for another 2h. The crude mixture was partitioned between EA and 2 N hydrochloricacid, the aqueous phase extracted with EA, and the combined organicphases were dried over magnesium sulfate, filtered and evaporated todryness. The residue was purified by silica gel chromatography (HEP/EAgradient) to yield 600 mg of the title compound.

LC/MS (Method LC14): Rt=3.00 min; m/z=300.1 [(M+CH₃CN+H)⁺]

Step 2 2-(4-Methoxy-3-o-tolyloxy-benzoylamino)-indane-2-carboxylic acid

The compound of step 1 was reacted with 2-amino-indane-2-carboxylic acidmethyl ester hydrochloride in analogy to step 2 of example 13. Theobtained ester was hydrolyzed in analogy to example 2.

LC/MS (Method LC12): Rt=3.57 min; m/z=418.1 [MH⁺]

EXAMPLE 239 2-(4-Methoxy-3-m-tolyloxy-benzoylamino)-indane-2-carboxylicacid

The title compound was prepared in analogy to example 238 using m-cresolinstead of o-cresol.

LC/MS (Method LC12): Rt=3.54 min; m/z=418.1 [MH⁺]

EXAMPLE 2402-[4-Methoxy-3-(2-methyl-benzoyl)-benzoylamino]-indane-2-carboxylic acid

Step 1 4-Methoxy-3-(2-methyl-benzoyl)-benzoic acid methyl ester

4-Methoxybenzoic acid methyl ester (5.00 g, 30.1 mmol) and2-methylbenzoyl chloride (4.88 g, 31.6 mmol) were dissolved inchlorobenzene (10 ml), tin(IV) chloride (9.41 g, 36.1 mmol) was addedcautiously, and the mixture was heated to 140° C. for 3 h. The additionof the acid chloride and tin tetrachloride was repeated twice, and themixture subsequently heated to 140° C. for 3 h each time. The mixturewas poured onto 300 ml of ice/water and extracted with DCM. The combinedextracts were dried over magnesium sulfate, filtered and evaporated todryness. The residue was purified by silica gel chromatography (HEP/EAgradient) and subsequently by RP HPLC (water/ACN gradient) to yield 200mg of the title compound.

¹H-NMR: δ=8.12 (dd, 1H); 7.91 (d, 1H); 7.71 (d, 1H); 7.50-7.41 (m, 1H);7.31-7.22 (m, 2H); 7.06 (d, 1H); 3.81 (s, 3H); 3.72 (s, 3H); 2.42 (s,3H)

Step 22-[4-Methoxy-3-(2-methyl-benzoyl)-benzoylamino]-indane-2-carboxylic acid

The compound of step 1 was hydrolyzed in analogy to example 2 and theobtained acid reacted with 2-amino-indane-2-carboxylic acid methyl esterhydrochloride in analogy to step 2 of example 13. The obtained ester washydrolyzed in analogy to example 2.

LC/MS (Method LC14): Rt=3.16 min; m/z=430.1 [MH⁺]

EXAMPLE 2412-[3-(Hydroxy-o-tolyl-methyl)-4-methoxy-benzoylamino]-indane-2-carboxylicacid

The compound of example 240 (70 mg, 0.163 mmol) was dissolved in amixture of methanol (1.5 ml) and ethanol (1.5 ml) and cooled in an icebath. Sodium borohydride (18.9 mg, 0.49 mmol) was added in two batchesand the mixture reacted with ice cooling until completion (3 h). Thevolatiles were evaporated and the residue was partitioned betweendiethyl ether and 1 N hydrochloric acid. The aqueous phase was extractedwith diethyl ether, and the combined organic phases were dried andevaporated. The residue was purified by RP HPLC (water/ACN gradient) toyield 13 mg of the title compound.

LC/MS (Method LC12): Rt=3.22 min; m/z=432.2 [MH⁺]

EXAMPLE 2422-[4-Methoxy-3-(2-methyl-benzyl)-benzoylamino]-indane-2-carboxylic acid

The compound of example 241 (32 mg, 0.074 mmol) was dissolved in ethanol(10 ml), palladium (10%) on charcoal (10 mg) was added, and the mixturewas hydrogenated at room temperature for 1 h at a hydrogen pressure of 5bar. After completion of the reaction, the mixture was filtered oversilica gel and evaporated to dryness. The residue was triturated withdiethyl ether, filtered and dried in vacuo to yield 25 mg of the titlecompound.

LC/MS (Method LC14): Rt=3.45 min; m/z=416.3 [MH⁺]

EXAMPLE 243 2-[4-Methoxy-3-benzyl-benzoylamino]-indane-2-carboxylic acid

The title compound was prepared in analogy to examples 240, 241 and 242.LC/MS (Method LC14): Rt=3.33 min; m/z=402.2 [MH⁺]

EXAMPLE 2442-[4-Methoxy-3-(3-methyl-benzyl)-benzoylamino]-indane-2-carboxylic acid

The title compound was prepared in analogy to examples 240, 241 and 242.LC/MS (Method LC12): Rt=3.74 min; m/z=416.1 [MH⁺]

EXAMPLE 2452-[4-Methoxy-3-(4-methyl-benzyl)-benzoylamino]-indane-2-carboxylic acid

The title compound was prepared in analogy to examples 240, 241 and 242.LC/MS (Method LC12): Rt=3.68 min; m/z=416.2 [MH⁺]

EXAMPLE 2462-(3-{2-[3-(2-Amino-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylicacid

Step 12-(3-{2-[3-(2-Azido-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylicacid methyl ester

300 mg (0.613 mmol) of2-(3-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylicacid methyl ester (methyl ester intermediate of example 27) andtriphenylphosphine (0.241 g, 0.920 mmol) were dissolved in THF (5 ml)and cooled in an ice bath. Diphenylphosphoryl azide (0.258 g, 0.920mmol) and DIAD (0.198 g, 0.920 mmol) were added sequentially, the icebath was removed and the mixture was stirred for 2 h at roomtemperature. The mixture was evaporated to dryness and purified bysilica gel chromatography (HEP/EA gradient) to yield 0.188 g of thetitle compound.

LC/MS (Method LC14): Rt=3.68 min; m/z=515.3 [MH⁺]

Step 22-(3-{2-[3-(2-Amino-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylicacid methyl ester

The compound of step 1 (0.185 g, 0.360 mmol) and triphenylphosphine(0.149 g, 0.539 mmol) were dissolved in a mixture of 3 ml of THF and 3ml of water, and the solution was stirred overnight at room temperature.The mixture was evaporated to dryness and purified by silica gelchromatography (DCM/methanol/28% ammonia gradient, 70:30:0 to 0:100:0 to0:90:10) to yield 0.17 g of the title compound.

LC/MS (Method LC14): Rt=2.68 min; m/z=489.2 [MH⁺]

Step 32-(3-{2-[3-(2-Amino-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylicacid

The compound of step 2 (85 mg, 0.174 mmol) was hydrolyzed in analogy toexample 2 to yield 31 mg of the title compound.

LC/MS (Method LC12): Rt=2.68 min; m/z=475.2 [MH⁺]

EXAMPLE 2472-(3-{2-[3-(2-Acetylamino-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylicacid

The compound of Step 2 of example 246 (85 mg, 0.174 mmol) was dissolvedin acetic anhydride and stirred under reflux for 30 min. Water was addedin excess and the mixture was refluxed for 10 min. After cooling, themixture was extracted with EA, the combined extracts were dried oversodium sulfate and evaporated to dryness. The residue was purified by RPHPLC (water/ACN gradient) to yield the methyl ester of the titlecompound. Hydrolysis of this ester in analogy to example 2 yielded 17 mgof the title compound.

LC/MS (Method LC16): Rt=3.95 min; m/z=1031.2 [(2M−H)⁻]

EXAMPLE 2482-{3-[2-(3-Carbamoylmethyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

Step 1 (3-Methoxycarbonylmethyl-phenyl)-acetic acid

(3-Carboxymethyl-phenyl)-acetic acid (7.4 g, 38.1 mmol) was suspended inmethanol (20 ml). Thionyl chloride (4.5 g, 38 mmol) was added at about−30° C. (vigorous reaction), and the mixture subsequently stirred atroom temperature for 90 min. After completion of the reaction, themixture was evaporated to dryness to yield the diester as a yellow oil.This material was dissolved in methanol (20 ml), solid lithium hydroxide(0.948 g, 1 equivalent) was added and the mixture stirred at roomtemperature for 1 h. After evaporation of the methanol, the residue waspartitioned between 2 N hydrochloric acid and EA and the aqueous phaseextracted with EA. The combined organic phases were dried over sodiumsulfate and evaporated to dryness. The crude mixture of diester,monoester and dicarboxylic acid was purified by RP HPLC (water/ACNgradient) to yield 3.1 g of the title compound.

LC/MS (Method LC16): Rt=3.18 min; m/z=415.3 [(2M−H)⁻]

Step 2 (3-Carbamoylmethyl-phenyl)-acetic acid methyl ester

The compound of step 1 (0.4 g, 1.92 mmol) was dissolved in thionylchloride (2.7 ml) and stirred at 60° C. for 1 h. The volatiles wereevaporated, and the residue was dissolved in DCM and added to a stirredmixture of EA and 28% aqueous ammonia. After completion of the reaction,the mixture was partitioned between water and EA and the aqueous phaseextracted with EA. The combined organic phases were dried over sodiumsulfate and evaporated to dryness to yield 0.278 g of the titlecompound.

LC/MS (Method LC16): Rt=2.56 min; m/z=252.0 [(M+HCOOH—H)⁻]

Step 3 2-[3-(2-Hydroxy-ethyl)-phenyl]-acetamide

The compound of step 2 (0.151 g, 0.729 mmol) was dissolved in 0.5 ml ofTHF and added to a suspension of lithium aluminium hydride (58 mg, 1.46mmol) in THF (1.5 ml) at −78° C. After 2 min, diethyl ether (6 ml) wasadded, followed by EA (0.2 ml). After warming to room temperature, waterwas added slowly until the alumina salts formed a thick slurry fromwhich the supernatant could be decanted easily. The slurry was washedrepeatedly with EA. The combined extracts were dried with sodium sulfateand evaporated to dryness to yield 0.101 g of the title compound.

LC/MS (Method LC15): Rt=2.40 min; m/z=180.2 [MH⁺]

Step 42-{3-[2-(3-Carbamoylmethyl-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylicacid

The compound of step 3 was transformed into the title compound inanalogy to step 3 of example 15, followed by hydrolysis in analogy toexample 2.

LC/MS (Method LC12): Rt=2.93 min; m/z=489.3 [MH⁺]

EXAMPLE 2492-(3-{2-[3-(2-Hydroxy-2-methyl-propyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylicacid

Step 1 [3-(2-Hydroxy-2-methyl-propyl)-phenyl]-acetic acid

(3-Methoxycarbonylmethyl-phenyl)-acetic acid (500 mg, 2.40 mmol) wasdissolved in THF (3.5 ml) and methylmagnesium chloride (2.8 ml, 3 Msolution in THF) was added slowly at room temperature. After stirringfor 30 min the reaction was completed.

Water was added cautiously and the mixture was partitioned between EAand 2 N hydrochloric acid. The aqueous phase was extracted with EA andthe combined organic phases were dried over sodium sulfate andevaporated to dryness. The residue was purified by RP HPLC (water/ACNgradient) to yield 0.34 g of the title compound.

LC/MS (Method LC16): Rt=2.92 min; m/z=415.2 [(2M−H]⁻]

Step 2 1-[3-(2-Hydroxy-ethyl)-phenyl]-2-methyl-propan-2-ol

The compound of step 1 (0.132 g, 0.634 mmol) was dissolved in THF (0.5ml) and added to a refluxing suspension of lithium aluminium hydride(122 mg, 3.1 mmol) in THF (1 ml). The mixture was stirred for 1 h underreflux and cooled to room temperature. Diethyl ether (6 ml) was added,followed by EA (0.4 ml). Subsequently, water was added slowly until thealumina salts formed a thick slurry from which the supernatant could bedecanted easily. The slurry was repeatedly washed with EA, the combinedextracts were dried with sodium sulfate and evaporated to dryness.

The residue was purified by RP HPLC (water/ACN gradient) to yield 49 mgof the title compound.

¹H-NMR: δ=7.15 (t, 1H); 7.06-7.00 (m, 3H); 4.59 (t, 1H); 4.23 (s, 1H);3.58 (dt, 2H); 2.69 (t, 2H); 2.60 (s, 2H); 1.04 (s, 6H)

Step 32-(3-{2-[3-(2-Hydroxy-2-methyl-propyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylicacid

The compound of step 2 was transformed into the title compound inanalogy to step 3 of example 15, followed by hydrolysis in analogy toexample 2.

LC/MS (Method LC14): Rt=3.05 min; m/z=504.2 [MH⁺]

EXAMPLE 2502-[4-Methoxy-3-(3-phenyl-oxetan-3-ylmethoxy)-benzoylamino]-indane-2-carboxylis acid

The compound of step 2 of example 15 and (3-phenyl-oxetan-3-yl)-methanol(S. Kanoh et al., Tetrahedron 58 (2002), 7065-7074) were reacted inanalogy to step 3 of example 15, and the obtained methyl ester washydrolyzed in analogy to example 16.

LC/MS (Method LC14): Rt=3.10 min; m/z=474.4 [MH⁺]

EXAMPLE 2512-{3-[2-(3-Hydroxy-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

Step 1 Acetic acid 3-(2-hydroxy-ethyl)-phenyl ester

2-(3-Hydroxyphenyl)ethanol (400 mg, 2.90 mmol) was dissolved in amixture of 4 ml of dioxane and 4 ml of water, and sodiumhydrogencarbonate (2.43 g, 29 mmol) was added followed by aceticanhydride (2.96 g, 29 mmol) with ice cooling. The mixture was stirredovernight at room temperature and then partitioned between 2 Nhydrochloric acid and EA. The aqueous phase was extracted with EA, thecombined organic phases were dried over sodium sulfate and evaporated todryness to yield the crude title compound which was used without furtherpurification.

Step 22-{3-[2-(3-Hydroxy-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid

The compound of step 1 and the compound of step 2 of example 15 werereacted in analogy to step 3 of example 15 and the obtained esterhydrolyzed in analogy to example 16.

LC/MS (Method LC12): Rt=3.17 min; m/z=448.2 [MH⁺]

EXAMPLE 2522-[3-Methoxy-4-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid

Step 1 3-Acetoxy-4-hydroxy-benzoic acid ethyl ester

3,4-Dihydroxy-benzoic acid ethyl ester (550 mg, 3.02 mmol) was dissolvedin DMF (5 ml), potassium tert-butoxide (210 mg, 2.87 mmol) was added andthe mixture stirred for 10 min. Acetic anhydride (339 mg, 3.32 mmol) wasadded and stirring continued for 10 min. The mixture was partitionedbetween EA and 2 N hydrochloric acid, and the aqueous phase extractedwith EA. The combined organic phases were dried over sodium chloride,decanted and evaporated to dryness. The residue was purified by RP HPLC(water/ACN gradient).

LC/MS (Method LC15): Rt=3.97 min; m/z=225.2 [MH⁺]

Step 2 3-Acetoxy-4-(2-m-tolyl-ethoxy)-benzoic acid ethyl ester

The compound of step 1 (350 mg, 1.56 mmol) was reacted with2-m-tolyl-ethanol in analogy to step 3 of example 15 to yield 450 mg ofthe title compound.

LC/MS (Method LC14): Rt=3.86 min; m/z=343.2 [MH⁺]

Step 3 3-Methoxy-4-(2-m-tolyl-ethoxy)-benzoic acid methyl ester

The compound of step 2 (150 mg, 0.438 mmol) was dissolved in methanol (3ml), potassium tert-butoxide (73 mg, 0.657 mmol) was added and themixture was stirred overnight under reflux. Potassium carbonate (60 mg,0.44 mmol) and iodomethane (124 mg, 0.876 mmol) were then addedrepeatedly, at intervals of 1 h, with stirring under reflux untilcompletion of the reaction. The volatiles were evaporated in vacuo, theresidue was partitioned between EA and 2 N hydrochloric acid, and theaqueous phase was extracted with EA. The combined organic phases weredried over sodium chloride, decanted and evaporated to dryness to yieldthe title compound.

LC/MS (Method LC15): Rt=5.27 min; m/z=301.2 [MH⁺]

Step 42-[3-Methoxy-4-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid

The compound of step 3 was hydrolyzed in analogy to example 2, theobtained carboxylic acid reacted with 2-amino-indane-2-carboxylic acidmethyl ester in analogy to step 1 of example 15, and the obtained esterhydrolyzed in analogy to example 2.

LC/MS (Method LC14): Rt=3.41 min; m/z=446.1 [MH⁺]

EXAMPLE 2532-[4-Benzyloxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

Step 1 3-Acetoxy-4-benzyloxy-benzoic acid ethyl ester

The compound of step 1 of example 252 (20 g, 89.2 mmol) was dissolved inDMF (100 ml) and cooled in an ice bath. Potassium carbonate (18.4 g, 134mmol) and, immediately thereafter, benzyl bromide (15.2 g, 89.2 mmol)were added. The mixture was stirred for 30 min at room temperature,filtered into a mixture of 2 N hydrochloric acid and diethyl ether. Thesolid was washed repeatedly with diethyl ether. The combined etherealphases were washed with water, dried over sodium chloride, decanted andevaporated to dryness. The residue was purified by silica gelchromatography (HEP/EA gradient) to yield 21 g of the title compound.

LC/MS (Method LC14): Rt=3.68 min; m/z=315.1 [MH⁺]

Step 2 4-Benzyloxy-3-hydroxy-benzoic acid ethyl ester

The compound of step 1 (10 g, 31.8 mmol) was dissolved in methanol,potassium carbonate (88 mg, 0.636 mmol) was added and the mixture wasstirred for 2 h under reflux. After evaporation to dryness, the residuewas used without further purification in the subsequent step.

LC/MS (Method LC14): Rt=3.32 min; m/z=273.1 [MH⁺]

Step 32-[4-Benzyloxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid methyl ester

The compound of step 2 was reacted with 2-m-tolyl-ethanol in analogy tostep 1 of example 1, and the obtained ester was hydrolyzed in analogy toexample 2. The obtained carboxylic acid was reacted with2-amino-indane-2-carboxylic acid methyl ester in analogy to step 2 ofexample 13.

LC/MS (Method LC14): Rt=4.05 min; m/z=536.3 [MH⁺]

Step 42-[4-Benzyloxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The compound of step 3 was hydrolyzed in analogy to example 2. LC/MS(Method LC14): Rt=3.79 min; m/z=522.2 [MH^(+])

EXAMPLE 2542-[4-Hydroxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid

Step 12-[4-Hydroxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acidmethyl ester

The compound of step 3 of example 253 (800 mg, 1.49 mmol) was dissolvedin EA (15 ml) and hydrogenated in the presence of palladium (10%) oncharcoal (200 mg) at a hydrogen pressure of 5 bar and room temperaturefor 6 h. The mixture was filtered over silica gel and evaporated todryness. The residue was purified by RP HPLC (water/ACN gradient) toyield 300 mg of the title compound.

LC/MS (Method LC14): Rt=3.47 min; m/z=446.2 [MH⁺]

Step 22-[4-Hydroxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid

The compound of step 1 was hydrolyzed in analogy to example 2. LC/MS(Method LC14): Rt=3.22 min; m/z=432.2 [MH⁺]

EXAMPLE 2552-[4-Isopropoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The compound of step 1 of example 254 was reacted with 2-propanol inanalogy to step 1 of example 1 and the obtained ester hydrolyzed inanalogy to example 2.

LC/MS (Method LC14): Rt=3.71 min; m/z=474.2 [MH⁺]

In analogy to example 255, the following example compounds of theformula Iw listed in table 9 were prepared by using the respectivealcohol instead of 2-propanol. In the formulae of the groups R⁹⁹ intable 9 the line crossed with the symbol

represents the free bond via which the group R⁹⁹ is bonded to the oxygenatom which is attached to the 4-position of the benzoyl group depictedin formula Iw. I.e., in the formula of the complete molecule theterminal endpoint of the line crossed with the said symbol ends at theoxygen atom attached to the 4-position of the benzoyl group. Thecompounds can be named as2-[4-(R⁹⁹-oxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid, for example as2-[4-cyclopropylmethoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid in the case of example 266.

TABLE 9 Example compounds of the formula Iw       Example

    LC/MS Method     m/z [MH⁺]   Retention time [min] 256

LC21 488.3 (a)  4.67 257

LC21 526.4 (a)  5.15 258

LC21 514.3 (a)  4.69 259

LC21 530.3 (a)  4.88 260

LC21 526.2 (a)  4.82 261

LC2 516.2  4.42 262

LC2 500.2  4.29 263

LC12 502.2  4.35 264

LC12 530.2  3.95 265

LC12 503.2  2.87 266

LC12 486.2  3.93 267

LC12 506.2  3.97 268

LC20 478.2 11.26 269

LC12 472.2  3.93 (a) [(M − H)⁻] instead of [MH⁺]

EXAMPLE 2702-[4-(2-Hydroxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

Step 12-[4-(2-Acetoxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The compound of step 1 of example 254 (70 mg, 0.157 mmol) was dissolvedin DMF (1 ml). Potassium carbonate (108 mg, 0.786 mmol) was added andsubsequently 2-bromoethyl acetate (39 mg, 0.235 mmol). The mixture wasstirred at room temperature for 2 h and then partitioned between EA andwater. The aqueous phase was extracted with EA, and the combined organicphases were dried over sodium sulfate and evaporated to dryness. Theresidue was purified by RP HPLC (water/ACN gradient).

LC/MS (Method LC18): Rt=2.59 min; m/z=532.2 [MH⁺]

Step 22-[4-(2-Hydroxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The compound of step 1 was hydrolyzed in analogy to example 2 using 6equivalents lithium hydroxide.

LC/MS (Method LC18): Rt=2.21 min; m/z=476.2 [MH⁺]

EXAMPLE 2712-[4-Carboxymethoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The title compound was prepared in analogy to example 270 from thecompound of step 1 of example 254 and 2-bromo-acetamide. In the finalhydrolysis step, 6 equivalents of lithium hydroxide were used, resultingin the hydrolysis of the ester moiety and the acetamide moiety.

LC/MS (Method LC18): Rt=2.23 min; m/z=490.1 [MH⁺]

EXAMPLE 2722-[4-Cyclopropoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

Step 12-[4-(1-Phenylsulfanyl-cyclopropoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

The compound of step 1 of example 254 (50 mg, 0.116 mmol),(1-iodo-cyclopropylsulfanyl)-benzene (G. J. Hollingworth et al.,Tetrahedron Lett. 40 (1999), 2633-2636) (64 mg, 0.232 mmol) and silvercarbonate (64 mg, 0.232 mmol) in toluene (1 ml) were stirred overnightat 50° C. The mixture was filtered, the filtrate evaporated to drynessand the residue purified by silica gel chromatography (HEP/EA gradient)to yield 44 mg of the title compound.

LC/MS (Method LC14): Rt=4.23 min; m/z=594.2 [MH⁺]

Step 22-[4-Cyclopropoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

3-Chloroperbenzoic acid (43 mg, 0.177 mmol) was added to the compound ofstep 1 (35 mg, 0.059 mmol) in DCM (2 ml) and saturated aqueous sodiumhydrogencarbonate solution (2 ml). The mixture was stirred for 30 min atroom temperature and then partitioned between EA and a sodium carbonatesolution. The aqueous phase was extracted with EA and the combinedorganic phases were dried over sodium sulfate and evaporated to dryness.The residue (44 mg) was dissolved in a mixture of 0.5 ml of THF and 1 mlof methanol. Disodium hydrogenphosphate (40 mg, 0.28 mmol) and sodiummercury amalgam (5% sodium) (250 mg) were added and the mixture wasstirred for 30 min at room temperature and stored for 6 days at 5° C.Then the mixture was partitioned between 2 N hydrochloric acid and EA,the aqueous phase extracted with EA, and the combined organic extractswere dried over sodium chloride, decanted and evaporated to dryness. Theresidue was purified by silica gel chromatography (DCM/methanol/28%ammonia gradient, 90:10:1 to 85:15:1.5). The product fractions wereevaporated to dryness and the residue partitioned between 2 Nhydrochloric acid and EA. The aqueous phase was extracted with EA, andthe combined organic extracts were dried over sodium chloride, decantedand evaporated to dryness.

LC/MS (Method LC14): Rt=3.60 min; m/z=472.2 [MH⁺]

EXAMPLE 2732-{[5-Ethyl-4-(2-m-tolyl-ethoxy)-thiazole-2-carbonyl]-amino}-indane-2-carboxylicacid

5-Ethyl-4-hydroxy-thiazole-2-carboxylic acid ethyl ester (F. A. J.Kerdesky et al., J. Med. Chem. 34 (1991), 2158-2165) (100 mg, 0.497mmol) was reacted with 2-m-tolyl-ethanol in analogy to step 1 of example1 and subsequently the ester moiety hydrolyzed in analogy to example 2.The obtained carboxylic acid was reacted with2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogyto step 2 of example 13 and the obtained ester hydrolyzed in analogy toexample 2.

LC/MS (Method LC12): Rt=4.17 min; m/z=451.2 [MH⁺]

EXAMPLE 2742-({5-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-indane-2-carboxylicacid

The title compound was prepared in analogy to example 208 using2-(2-fluoro-5-methyl-phenyl)-ethanol instead of 2-m-tolyl-ethanol.

LC/MS (Method LC12): Rt=3.64 min; m/z=465.2 [MH⁺]

EXAMPLE 2752-[(5-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)-amino]-indane-2-carboxylicacid

6-Chloro-5-nitro-nicotinic acid methyl ester was prepared according tothe procedure described in WO 2005/021544 and transformed into5-hydroxy-6-methoxy-nicotinic acid methyl ester according to theprocedure described in WO 95/04045. The latter compound was transformedinto the title compound by etherification with2-[3-(2-hydroxy-ethyl)-phenyl]-ethanol in analogy to step 1 of example1, hydrolysis of the ester group in analogy to example 2, reaction ofthe obtained carboxylic acid with 2-amino-indane-2-carboxylic acidmethyl ester hydrochloride in analogy to step 3 of example 1, andhydrolysis of the ester group in analogy to example 2.

LC/MS (Method LC14): Rt=2.90 min; m/z=477.2 [MH⁺]

EXAMPLE 2762-(3-Fluoro-5-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylicacid

Step 1 Acetic acid 2-[3-(2-hydroxy-ethyl)-phenyl]-ethyl ester

2-[3-(2-Hydroxy-ethyl)-phenyl]-ethanol (2.49 g, 15.0 mmol) was dissolvedin ACN (5 ml) and acetic anhydride (3.06 g, 30 mmol) added. The mixturewas stirred under reflux for 1 h and then evaporated to dryness. Silicagel chromatography (HEP/EA gradient) of the residue yielded 1.30 g ofthe title compound (mono-acetylated product).

¹H-NMR: δ=7.20 (t, 1H); 7.10-7.05 (m, 3H); 4.61 (t, 1H); 4.19 (t, 2H);3.59 (dt, 2H); 2.82 (t, 2H); 2.69 (t, 2H); 1.98 (s, 3H)

Step 2 2-Fluoro-3-hydroxy-4-methoxybenzoic acid methyl ester and3-fluoro-5-hydroxy-4-methoxybenzoic acid methyl ester

3-Acetoxy-4-methoxy-benzoic acid methyl ester (WO 2005/009389) (3.58 g,16.0 mmol) and 1-chloromethyl-4-fluoro-1.4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (Selectfluor®) (14.1 g, 39.9 mmol) in ACN werebatchwise (7 batches) heated to 170° C. for 7 min in a microwavereactor. The combined batches were partitioned between 2 N hydrochloricacid and diethyl ether. The aqueous phase was extracted with diethylether, the combined organic phases were dried over sodium sulfate,filtered and evaporated to dryness. The residue was purified by silicagel chromatography (HEP/EA gradient) to yield 0.7 g of a mixture of theisomeric fluorinated compounds with and without an acetyl group. Thismixture was dissolved in methanol (5 ml) and, after addition ofpotassium carbonate (80 mg), heated under reflux for 3 h. Afterevaporation to dryness, the residue was partitioned between 2 Nhydrochloric acid and EA, the aqueous phase extracted with EA, and thecombined extracts were dried over sodium sulfate and evaporated todryness. The residue was separated by RP HPLC (water/ACN gradient) toyield 0.14 g of 2-fluoro-3-hydroxy-4-methoxybenzoic acid methyl esterand 0.27 g of 3-fluoro-5-hydroxy-4-methoxybenzoic acid methyl ester.

2-Fluoro-3-hydroxy-4-methoxybenzoic acid methyl ester:

¹H-NMR: δ=10.55 (s, 1H); 7.61 (dd, 1H); 6.80 (dd, 1H); 3.90 (s, 3H);3.88 (s, 3H)

3-Fluoro-5-hydroxy-4-methoxybenzoic acid methyl ester:

¹H-NMR: δ=10.25 (s, 1H); 7.30 (br s, 1H); 7.21 (dd, 1H); 3.87 (s, 3H);3.81 (s, 3H)

Step 32-(3-Fluoro-5-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylicacid

The title compound was prepared from 3-fluoro-5-hydroxy-4-methoxybenzoicacid methyl ester by etherification with the compound of step 1 inanalogy to step 1 of example 1, hydrolysis of both ester moieties of theobtained compound with 6 equivalents of lithium hydroxide in analogy toexample 2, reaction of the obtained carboxylic acid with2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogyto step 3 of example 1, and hydrolysis of the methyl ester in analogy toexample 2.

LC/MS (Method LC14): Rt=3.11 min; m/z=494.2 [MH⁺]

EXAMPLE 2772-[2-Fluoro-4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid

2-Fluoro-3-hydroxy-4-methoxybenzoic acid methyl ester was etherifiedwith 2-m-tolyl-ethanol in analogy to step 1 of example 1, the obtainedester hydrolyzed in analogy to example 2, the obtained carboxylic acidreacted with 2-amino-indane-2-carboxylic acid methyl ester hydrochloridein analogy to step 3 of example 1, and the methyl ester hydrolyzed inanalogy to example 2.

LC/MS (Method LC14): Rt=3.92 min; m/z=464.2 [MH⁺]

EXAMPLE 2782-{4-Methoxy-3-[2-(3-methyl-cyclohexyl)-ethoxy]-benzoylamino}-indane-2-carboxylicacid

Step 1 4-Methoxy-3-[2-(3-methyl-cyclohexyl)-ethoxy]-benzoic acid

The compound of step 1 of example 13 (100 mg) was dissolved in ethanol(5 ml). Platinum(IV) oxide (12 mg) was added, the mixture washydrogenated for 1 h at room temperature at a hydrogen pressure of 1bar, filtered over celite and evaporated to dryness to yield 99 mg ofthe title compound.

LC/MS (Method LC12): Rt=3.87 min; m/z=334.2 [(M+CH₃CN+H)⁺]

Step 22-{4-Methoxy-3-[2-(3-methyl-cyclohexyl)-ethoxy]-benzoylamino}-indane-2-carboxylicacid

The compound of step 1 was reacted with 2-amino-indane-2-carboxylic acidmethyl ester hydrochloride in analogy to step 4 of example 3 and theobtained ester hydrolyzed in analogy to example 2.

LC/MS (Method LC18): Rt=2.72 min; m/z=452.2 [MH⁺]

EXAMPLE 2792-[4-Methoxy-3-(3-methyl-benzyloxymethyl)-benzoylamino]-indane-2-carboxylicacid

Step 1 2-(3-Formyl-4-methoxy-benzoylamino)-indane-2-carboxylic acidmethyl ester

3-Formyl-4-methoxy-benzoic acid (F. D. Chattaway and F. Calvet, J. Chem.Soc. (1928), 2913-2918) (1.017 g, 5.65 mmol) was reacted with2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogyto step 4 of example 3. The obtained product (1.895 g) was dissolved inacetic acid (20 ml), sodium acetate (0.57 g, 6.96 mmol) was added andthe mixture was stirred under reflux for 24 h. The volatiles wereevaporated in vacuo, the residue partitioned between a saturated sodiumhydrogencarbonate solution and EA, and the aqueous phase extracted withEA. The combined organic phases were dried over sodium sulfate andevaporated to dryness to yield 1.52 g of the title compound.

LC/MS (Method LC14): Rt=3.00 min; m/z=354.1 [MH⁺]

Step 2 2-(3-Hydroxymethyl-4-methoxy-benzoylamino)-indane-2-carboxylicacid methyl ester

The compound of step 1 (0.500 g, 1.42 mmol) was dissolved in THF (5 ml)and cooled in an ice bath. Sodium borohydride (0.164 g, 4.25 mmol) wasadded. Subsequently methanol (2 ml) was added dropwise. After 1 h, thevolatiles were evaporated, the residue was partitioned between diethylether and a saturated sodium hydrogencarbonate solution, and the aqueousphase extracted with diethyl ether. The combined organic phases weredried over sodium sulfate and evaporated to dryness.

LC/MS (Method LC14): Rt=2.74 min; m/z=356.1 [MH⁺]

Step 32-[4-Methoxy-3-(3-methyl-benzyloxymethyl)-benzoylamino]-indane-2-carboxylicacid

The compound of step 2 (50 mg, 0.14 mmol)) was dissolved in DMF (3 ml)and sodium hydride (60% dispersion in mineral oil, 6.2 mg, 0.15 mmol)was added followed by 1-bromomethyl-3-methyl-benzene (27 mg, 0.14 mmol).The mixture was stirred overnight. Then lithium hydroxide (1 M solutionin water, 0.42 ml) and dioxane (1 ml) were added and the mixture heatedto 60° C. for 1 h. The residue was partitioned between 2 N hydrochloricacid and EA and the aqueous phase was extracted with EA. The combinedorganic phases were dried over sodium sulfate and evaporated to dryness.The residue was purified by RP HPLC (water/ACN gradient) to yield 5 mgof the title compound.

LC/MS (Method LC14): Rt=3.44 min; m/z=446.2 [MH⁺]

In analogy to example 196, the example compounds of the formula Iulisted in table 10 were prepared by using the respective substitutedphenylboronic acid instead of 3-isopropylphenylboronic acid. In the caseof examples 282, 283 and 284, the intermediary2-[3-(R⁹⁷)-4-methoxy-benzoylamino]-indane-2-carboxylic acid methyl esterwas purified by preparative RP HPLC (water/ACN gradient) beforehydrolysis. The compounds can be named as2-[3-(R⁹⁷)-4-methoxy-benzoylamino]-indane-2-carboxylic acid, for exampleas2-[3-(5-chloro-pyridin-3-yl)-4-methoxy-benzoylamino]-indane-2-carboxylicacid in the case of example 282.

TABLE 10 Example compounds of the formula Iu LC/MS m/z Retention ExampleR⁹⁷ Method [MH⁺] time [min] 280 4-chloro-phenyl LC22 422.22 2.37 2812-chloro-phenyl LC22 422.22 2.17 282 5-chloro-pyridin-3-yl LC14 423.082.93 283 6-cyano-pyridin-2-yl LC12 414.19 3.17 284 5-cyano-pyridin-3-ylLC14 414.15 2.85

EXAMPLE 285

General procedure for the preparation of2-(3-aryl-4-methoxy-benzoylamino)-indane-2-carboxylic acids

0.3 mmol of the respective boronic acid were weighed into a microwavereaction vial. 0.2 mmol of2-(3-bromo-4-methoxy-benzoylamino)-indane-2-carboxylic acid methyl esterin 2 ml of 1,2-dimethoxyethane and 0.4 mmol of cesium fluoride in 1 mlof methanol were added, followed by 0.01 mmol oftetrakis(triphenylphosphine)palladium(0) in 0.5 ml of methanol. The vialwas closed with a crimp cap and irradiated in a microwave reactor at130° C. for 5 min. The cooled solution was treated with 0.25 ml of 4 Naqueous sodium hydroxide and irradiated for another 5 min at 130° C. ina microwave reactor. The cooled solution was neutralized with 0.25 ml of4 N aqueous hydrochloric acid and evaporated. The residue was dissolvedin 2 ml of DMF, filtered and submitted to preparative RP HPLC (water/ACNgradient).

According to the general procedure described in example 285, thecompounds of the formula Iu listed in table 11 were prepared. They canbe named as 2-[3-(R⁹⁷)-4-methoxy-benzoylamino]-indane-2-carboxylic acid,for example as2-[(3′-ethanesulfonyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylicacid in the case of example 312 in which the group R⁹⁷ is3-ethanesulfonyl-phenyl and, in view of the rules of nomenclature, thegroup 3-(R⁹⁷)-4-methoxy-phenyl-C(O) depicted in formula Iu thus is named3′-ethanesulfonyl-6-methoxy-biphenyl-3-carbonyl.

TABLE 11 Example compounds of the formula Iu Ex- am- LC/MS m/z Retentionple R⁹⁷ Method [MH⁺] time [min] 286 3-methyl-phenyl LC13 402.21 2.55 2873-acetylamino-phenyl LC13 445.23 2.14 288 3-ethoxy-phenyl LC13 432.212.55 289 2-chloro-5-trifluoromethyl-phenyl LC13 490.12 2.70 2904-propyl-phenyl LC13 430.22 2.80 291 3,4-dimethyl-phenyl LC13 416.222.63 292 3,4-dichloro-phenyl LC13 456.12 2.75 293 2,3-dichloro-phenylLC13 456.12 2.61 294 4-methoxy-3,5-dimethyl-phenyl LC13 446.22 2.57 295benzo[b]thiophen-3-yl LC12 444.2 3.65 296 5-chloro-2-methoxy-phenyl LC13452.17 2.53 297 3-cyano-phenyl LC13 413.19 2.39 2983-dimethylamino-phenyl LC13 472.27 1.88 299 2-dimethylaminomethyl-phenylLC13 445.22 1.87 300 4-methyl-thiophen-2-yl LC13 408.16 2.54 3013-methylsulfanyl-phenyl LC13 434.18 2.56 302 3-trifluoromethoxy-phenylLC13 472.14 2.70 303 2,5-dichloro-phenyl LC13 456.12 2.64 3045-fluoro-2-methoxy-phenyl LC13 436.18 2.43 305 3-benzyloxy-phenyl LC13494.24 2.76 306 3,4,5-trifluoro-phenyl LC13 442.14 2.63 3073-methanesulfonylamino-phenyl LC13 481.19 2.20 3083-ethylsulfanyl-phenyl LC13 448.19 2.67 309 3-methanesulfonyl-phenylLC13 466.18 2.21 310 4-chloro-3-trifluoromethyl-phenyl LC13 490.12 2.79311 3-(pyrrolidin-1-yl)-phenyl LC13 498.27 2.22 3123-ethanesulfonyl-phenyl LC13 480.19 2.28 3133-tert-butyl-5-methyl-phenyl LC13 458.25 2.91 3145-chloro-2-methyl-phenyl LC12 436.19 3.74 315 3-methoxymethyl-phenylLC13 432.21 2.40 316 2-methoxymethyl-phenyl LC12 432.25 3.34 3172,4,5-trimethyl-phenyl LC13 430.22 2.69 318 3-propoxy-phenyl LC13 446.232.68 319 3-isopropoxy-phenyl LC13 446.18 2.58 3202-fluoro-5-trifluoromethyl-phenyl LC13 474.01 2.60 3213-chloro-4-propoxy-phenyl LC13 480.08 2.76 3223-chloro-4-trifluoromethyl-phenyl LC13 490.01 2.75 3233-methylcarbamoyl-phenyl LC13 445.12 2.08 3243-cyclopropylmethoxy-phenyl LC13 458.12 2.61 3253-chloro-4-methoxy-phenyl LC13 452.12 2.49 326 benzofuran-5-yl LC13428.14 2.46 327 3-chloro-2-methyl-phenyl LC13 436.12 2.61 3283-(2-carboxy-ethyl)-phenyl LC13 460.22 2.21 329 2-chloro-thiophen-3-ylLC13 428.09 2.45 330 1-methyl-1H-indol-5-yl LC13 441.21 2.44 3312-ethoxy-naphthalen-1-yl LC13 482.21 2.58 332 5-chloro-2-fluoro-phenylLC13 440.11 2.53 333 5-chloro-2-fluoro-3-methyl-phenyl LC13 454.12 2.63334 3-(pyrazol-1-yl)-phenyl LC13 454.16 2.37 3355-fluoro-2-isopropoxy-phenyl LC13 464.19 2.56 3362-fluoro-5-isopropoxy-phenyl LC13 464.16 2.57 3375-fluoro-3-trifluoromethyl-phenyl LC13 474.09 2.68 3383-dimethylaminomethyl-phenyl LC13 445.18 1.84 3393-(acetylamino-methyl)-phenyl LC13 459.23 2.11 3404-ethoxy-3-methyl-phenyl LC13 446.23 2.69 3414-isopropoxy-3-methyl-phenyl LC13 460.24 2.78 3423-chloro-5-fluoro-phenyl LC13 440.13 2.66 3435-fluoro-3-isopropoxy-phenyl LC13 464.21 2.71 3445-fluoro-3-isobutoxy-phenyl LC13 478.22 2.88 3454-fluoro-3-trifluoromethyl-phenyl LC13 474.17 2.68 3463-(2,2,2-trifluoro-ethoxy)-phenyl LC12 486.22 3.68 3475-chloro-3-trifluoromethyl-phenyl LC13 490.13 2.83 3482-fluoro-3-trifluoromethyl-phenyl LC13 474.13 2.63 3495-methoxy-3-trifluoromethyl- LC13 486.16 2.69 phenyl 3503-isobutyrylamino-phenyl LC12 473.28 3.30 3515-chloro-2-trifluoromethyl-phenyl LC13 490.12 2.68

In analogy to the examples listed in table 1, the example compounds ofthe formula Im listed in table 12 were prepared. In the formulae of thegroups R⁹⁰ in table 12 the line crossed with the symbol

represents the free bond via which the group R⁹⁰ is bonded to the oxygenatom which is attached to the 3-position of the benzoyl group depictedin formula Im. I.e., in the formula of the complete molecule theterminal endpoint of the line crossed with the said symbol ends at theoxygen atom attached to the 3-position of the benzoyl group. Thecompounds can be named as2-[3-(R⁹⁰-oxy)-4-methoxy-benzoylamino]-indane-2-carboxylic acid, forexample as2-{3-[2-(2-fluoro-5-trifluoromethoxy-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid in the case of example 355.

TABLE 12 Example compounds of the formula Im   Ex- am- ple

LC/ MS Meth- od     m/z [MH⁺] Reten- tion time [min] 352

LC13 500.04 2.77 353

LC13 438.13 2.25 354

LC13 473.18 2.37 355

LC12 534.07 3.84

EXAMPLE 356 Starting Compound2-(2-Fluoro-5-trifluoromethoxy-phenyl)-ethanol

3.00 g (12.6 mmol) of 2-(2-fluoro-5-trifluoromethoxy-phenyl)-acetic acidwere dissolved in 50 ml of dry THF and dropped at 0° C. into asuspension of 956 mg (25.2 mmol) of lithium aluminium hydride in 11 mlof THF. After stirring overnight, 150 ml of THF were added followed by 3ml of EA. 15 ml water were added dropwise and the supernatant decantedfrom the resulting slurry. The slurry was extracted three times with 20ml of EA. The combined organic phases were dried over sodium sulfate andevaporated. The remaining oil (2.5 g) was used for the next step withoutfurther purification.

In analogy to example 356, the starting compounds2-(benzo[d]isoxazol-3-yl)-ethanol and 2-(4-methyl-furazan-3-yl)-ethanolwere prepared from 2-(benzo[d]isoxazol-3-yl)-acetic acid and2-(4-methyl-furazan-3-yl)-acetic acid, respectively.

EXAMPLE 3572-[(3′-Ethanesulfonyl-5-fluoro-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylicacid

Step 1 3-Bromo-5-fluoro-4-hydroxy-benzoic acid methyl ester

During 30 min, 5.64 g (35.27 mmol) of bromine were added to a solutionof 5.00 g (29.39 mmol) of 3-fluoro-4-hydroxy-benzoic acid methyl esterin 30 ml of DCM and 30 ml of acetic acid at 0° C. After stirringovernight, 200 ml of methyl acetate were added. The resulting solutionwas extracted with a solution of 7.56 g (60 mmol) of sodium sulfite in50 ml of water, a saturated sodium chloride solution and water. Theorganic phase was dried over sodium sulfate, filtered and evaporated.The resulting white solid (7.2 g) was used in the next step withoutfurther purification.

Step 2 3-Bromo-5-fluoro-4-methoxy-benzoic acid methyl ester

6 g (24.09 mmol) of the product obtained in step 1 were dissolved in 60ml of acetone, 10.13 g (2.270 mmol) of potassium carbonate and 6.84 g(48.18 mmol) of iodomethane were added, and the mixture was stirred for4 days. Then is was filtered and evaporated. The resulting product (5.8g) was used in the next step without further purification.

Step 3 3-Bromo-5-fluoro-4-methoxy-benzoic acid

5.8 g of the product obtained in step 2 were dissolved in 100 ml of amixture of THF and water (9:1), 1.06 g (44.1 mmol) of lithium hydroxidewere added and the mixture was stirred for 3 days. The solvent wasevaporated and the residue was purified by preparative RP HPLC(water/ACN gradient). 2.9 g of the title compound were obtained.

Step 4 2-(3-Bromo-5-fluoro-4-methoxy-benzoylamino)-indane-2-carboxylicacid methyl ester

2.4 g (9.64 mmol) of the compound of step 3 were dissolved in 40 ml ofDMF and 2.49 g (19.27 mmol) of EDIA and 4.03 g (10.60 mmol) of0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate were added. Then a solution of 2.19 g (9.64 mmol) of2-amino-indane-2-carboxylic acid methyl ester hydrochloride in 10 ml ofDMF was added. After stirring overnight, the mixture was evaporated todryness and the residue purified by preparative RP HPLC (water/ACNgradient). 3.6 g of the title compound were obtained.

Step 52-[(3′-Ethanesulfonyl-5-fluoro-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylicacid

300 mg (0.71 mmol) of the compound of step 4 and 175 mg (1.07 mmol) of3-ethanesulfonylphenylboronic acid were dissolved in 4 ml of DMF and 4ml of 1,2-dimethoxyethane under an argon atmosphere. 216 mg (1.42 mmol)of cesium fluoride and 41.08 mg (0.04 mmol) oftetrakis(triphenylphosphine)palladium(0) were added, and the mixture washeated to 130° C. in a microwave reactor for 15 min. After cooling, thesolvent was evaporated and the residue purified by preparative RP HPLC(water/ACN gradient) to yield the methyl ester of the title compound.135.1 mg (0.26 mmol) methyl ester were dissolved in 5 ml of a mixture ofTHF and water (9:1), 12.65 mg (0.53 mmol) of lithium hydroxide wereadded and the mixture was stirred for 3 days. The solvent was evaporatedand the residue was purified by preparative RP HPLC (water/ACNgradient). 123 mg of the title compound were obtained.

LC/MS (Method LC14): Rt=3.07 min; m/z=498.19 [MH⁺]

1H-NMR: δ=12.5 (br s, 1H); 8.90 (s, 1H); 7.98 (s, 1H); 7.75-7.95 (m,6H); 7.28 (d, 4H); 3.30-3.64 (m, 6H); 1.13 (t, 3H)

In analogy to example 357, the example compounds of the formula Ixlisted in table 13 were prepared by using the respective substitutedphenylboronic acid instead of 3-ethanesulfonylphenylboronic acid. Theycan be named as2-[3-(R¹⁰⁰)-5-fluoro-4-methoxy-benzoylamino]-indane-2-carboxylic acid,for example as2-[(5-fluoro-3′-isopropyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylicacid in the case of example 360 in which the group R¹⁰⁰ is3-isopropyl-phenyl and, in view of the rules of nomenclature, the group3-(R¹⁰⁰)-5-fluoro-4-methoxy-phenyl-C(O) depicted in formula Ix thus isnamed 5-fluoro-3′-isopropyl-6-methoxy-biphenyl-3-carbonyl.

TABLE 13 Example compounds of the formula Ix Exam- LC/MS m/z Retentionple R¹⁰⁰ Method [MH⁺] time [min] 358 4-chloro-phenyl LC14 440.15 3.53359 3-methanesulfonylamino-phenyl LC14 499.19 2.96 3603-isopropyl-phenyl LC14 448.22 4.08 361 3-dimethylaminosulfonylamino-LC14 528.21 3.28 phenyl

EXAMPLE 3622-{3-[2-(2,5-Dichloro-phenyl)-ethoxy]-4-trifluoromethyl-benzoylamino}-indane-2-carboxylicacid

The title compound was synthesized in analogy to example 185 by using2,5-dichloro-phenyl-ethanol instead of 2-(3-methyl-phenyl)-ethanol instep 3.

LC/MS (Method LC13): Rt=538,01 min; m/z=3.06 min [MH⁺]

Pharmacological Tests

A) Determination of Edg-2 receptor inhibition by fluorescence imagingplate reader (FLIPR) measurements

The inhibition of the Edg-2 receptor (LPA₁ receptor) by the compounds ofthe invention was quantified by the inhibitory effect on theLPA-mediated calcium liberation in a cell-based calcium fluorescenceassay by use of Chinese hamster ovarian (CHO) cells in which the humanEdg-2 receptor was stably overexpressed (Flp-In system, Invitrogen). Inorder to enforce G-Protein coupling and to direct signaling towardsCa²⁺liberation, the overexpressed receptor additionally had a C-terminalsequence of a modified G-protein (G_(αi4qi4)) (WO 02/04665). Changes inintracellular calcium were determined by fluorescence measurement withthe calcium-sensitive dye fluo-4 (Invitrogen) in a fluorescence imagingplate reader (FLIPR, Molecular Dynamics).

CHO cells stably overexpressing the human Edg-2 receptor were seeded(40.000 per well) in black clear-bottomed poly-D-lysine-coated 96 wellplates (Becton Dickinson, Biocoat cellware) approximately 18-24 h priorto the experiments. Cells were grown in an incubator at 37° C., 5%carbon dioxide and 95% humidity in cell culture media based on F-12glutamax media (Gibco, #31765) supplemented with 1% (vol/vol)penicilline/streptomycine (PAN, #P06-07100), 10% (vol/vol) fetal calfserum (FCS, PAA, #A15-151) and hygromycin B (Invitrogen, #10687-010) 300mg/l (final concentrations).

Prior to the FLIPR experiment, cells were loaded with fluo-4acetoxymethyl ester (fluo-4 AM, Invitrogen, #F14202) for 60 min in anincubator at 37° C., 5% carbon dioxide and 95% humidity in dye-loadingbuffer consisting of Hanks' Balanced Salt Solution (HBSS, Invitrogen,#14065049) supplemented with fluo-4 AM at 2 μM (all data given for finalconcentration), Pluronic® F-127 0.05% (vol/vol) (Invitrogen, #P-3000MP), HEPES 20 mM (Gibco, #15630), probenecid 2.5 mM (Sigma, #P-8761) andbovine serum albumin 0.05% (BSA, Sigma, #A-6003), adjusted to pH 7.5with sodium hydroxide. During cell loading, fluo-4 AM is cleaved byintracellular esterase resulting in trapping of the dye fluo-4 withinthe cells. Loading was terminated by washing of the cells in a cellwasher (Tecan Power washer) three times with the buffer specified aforebut without fluo-4 AM and BSA. This latter buffer was also used as thebuffer in the subsequent cell fluorescence measurements.

The dye-loaded and washed cells were pre-incubated for approximately 5min with various concentrations of the test compound added as a solutionin DMSO (0.3 vol/vol maximum final concentration of DMSO), or with DMSOin the respective concentration only (positive control). Subsequentaddition of LPA (18:1,1-oleoyl-sn-glycerol 3-phosphate; 100 nM finalconcentration) leads to liberation of intracellular calcium frominternal stores resulting in a large transient increase of the fluo-4fluorescence signal which was monitored over approximately 3 min. Thepercent inhibition caused by the test compound was determined from themaximum fluorescence response after LPA addition to cells pre-incubatedwith the compound as compared to the maximum fluorescence response afterLPA addition to cells pre-incubated with DMSO only. All fluorescencevalues were corrected for the baseline fluorescence values obtained withcells which were pre-incubated with DMSO only and were not treated withLPA (baseline control). All measurements were performed in triplicate.From the percent inhibitions the inhibitory concentration IC₅₀ wasdetermined.

Inhibitory concentrations IC₅₀ of various example compounds are given intable 14, wherein “a” denotes an IC₅₀ of less than 0.1 μM, “b” denotesan IC₅₀ between 0.1 μM and 1 μM, and “c” denotes an IC₅₀ between 1 μMand 30 μM.

TABLE 14 Inhibitory concentrations IC₅₀ for inhibition of the Edg-2receptor Example IC₅₀ 2 a 4 a 5 c 6 c 8 b 9 b 10 a 11 a 12 a 14 a 16 a17 c 18 c 19 a 20 a 21 a 22 c 23 a 24 a 25 a 26 c 27 a 28 c 29 c 30 c 31c 32 c 33 c 34 c 35 c 36 c 37 c 38 c 39 c 40 c 41 c 42 c 43 c 44 c 45 c46 b 47 c 48 c 49 c 50 b 51 c 52 c 53 c 54 c 55 c 56 c 57 c 58 c 59 c 60c 61 c 62 c 63 c 64 c 65 c 66 c 67 c 68 c 69 c 70 c 71 c 72 c 73 c 74 c75 c 76 c 77 c 78 c 79 c 80 c 81 a 82 c 83 c 84 c 85 c 86 c 87 c 88 c 89c 90 c 91 c 94 a 95 c 96 c 98 a 99 a 100 a 101 c 102 b 103 c 104 c 105 b106 a 107 c 108 b 109 c 110 c 111 c 112 c 113 c 114 c 115 c 116 a 117 b118 c 119 c 120 c 121 c 122 b 123 c 124 b 126 c 127 a 128 b 129 b 130 a131 a 132 a 133 b 134 c 135 c 136 c 137 c 138 c 139 b 140 c 141 c 142 c143 a 144 a 145 b 146 b 147 b 148 c 149 a 150 c 151 c 152 a 153 b 154 a155 c 156 a 157 a 158 b 159 a 161 c 162 c 163 b 164 a 165 b 166 b 167 c168 a 169 b 171 a 172 c 173 c 174 c 175 c 176 a 177 b 178 c 179 b 180 a181 a 182 c 183 c 184 c 185 a 186 a 187 a 188 a 189 a 190 c 191 a 192 a193 a 194 c 195 b 196 a 197 c 198 a 199 a 200 a 201 c 202 a 203 a 204 a205 c 206 c 207 c 208 a 209 a 210 b 211 a 212 a 213 a 214 a 215 a 216 a217 a 218 a 219 c 220 a 221 a 222 a 223 a 224 a 225 b 226 a 227 a 228 a229 a 230 a 231 a 232 a 233 a 234 a 235 a 236 a 237 b 238 b 239 c 240 c241 c 242 b 243 c 244 b 245 a 246 c 247 b 248 a 249 a 250 a 251 c 252 b253 a 254 c 255 a 256 a 257 a 258 a 259 a 260 b 261 b 262 a 263 a 264 a265 b 266 a 267 a 268 a 269 a 270 a 271 b 272 b 273 b 274 a 275 a 276 a277 c 278 c 279 b 280 b 281 c 282 b 283 c 284 a 286 a 287 b 288 b 289 b290 c 291 b 292 a 293 a 294 a 295 a 296 a 297 a 298 b 299 c 300 b 301 a302 a 303 a 304 a 305 b 306 a 307 a 308 a 309 b 310 b 311 c 312 b 313 a314 a 315 a 316 b 317 b 318 a 319 b 320 a 321 c 322 a 323 c 324 c 325 a326 b 327 a 328 b 329 c 330 c 331 b 332 b 333 a 334 b 335 a 336 c 337 a338 c 339 b 340 b 341 c 342 a 343 a 344 b 345 a 346 b 347 a 348 a 349 a350 c 351 a 352 a 353 c 354 c 355 a 357 a 358 a 359 a 360 a 361 a 362 a

B) In Vivo Antihypertrophic and Renoprotective Activity

The in vivo pharmacological activity of the compounds of the inventioncan be investigated, for example, in the model of DOCA-salt sensitiverats with unilateral nephrectomy. Briefly, in this model unilateralnephrectomy of the left kidney (UNX) is performed on Sprague Dawley ratsof 150 g to 200 g of body weight. After the operation as well as at thebeginning of each of the following weeks 30 mg/kg of body weight of DOCA(desoxycorticosterone acetate) are administered to the rats bysubcutaneous injection. The nephrectomized rats treated with DOCA aresupplied with drinking water containing 1% of sodium chloride (UNX/DOCArats). The UNX/DOCA rats develop high blood pressure, endothelialdysfunction, myocardial hypertrophy and fibrosis as well as renaldysfunction. In the test group (UNX/DOCA Test) and the placebo group(UNX/DOCA Placebo), which consist of randomized UNX/DOCA rats, the ratsare treated orally by gavage in two part administrations at 6 a.m. and 6p.m. with the daily dose of the test compound (for example 10 mg/kg ofbody weight dissolved in vehicle) or with vehicle only, respectively. Ina control group (control), which consists of animals which have not beensubjected to UNX and DOCA administration, the animals receive normaldrinking water and are treated with vehicle only. After five weeks oftreatment, systolic blood pressure (SBP) and heart rate (HR) aremeasured non-invasively via the tail cuff method. For determination ofalbuminuria and creatinine, 24 h urine is collected on metabolic cages.Endothelial function is assessed in excised rings of the thoracic aortaas described previously (W. Linz et al., JRAAS (Journal of therenin-angiotensin-aldosterone system) 7 (2006), 155-161). As a measureof myocardial hypertrophy and fibrosis, heart weight, left ventricularweight and the relation of hydroxyproline and proline are determined inexcised hearts.

1. A compound of formula I,

wherein ring A is a 3-membered to 7-membered cycloalkane ring, a benzenering, or a monocyclic 5-membered or 6-membered aromatic heterocyclicring which comprises 1 or 2 identical or different hetero ring memberschosen from the series consisting of N, N(R⁰), O and S, wherein thecycloalkane ring is optionally substituted by one or more identical ordifferent substituents chosen from the series consisting of fluorine and(C₁-C₄)-alkyl, and the benzene ring and the heterocyclic rings areoptionally substituted by one or more identical or differentsubstituents chosen from the series consisting of halogen, R¹, HO—,R¹—O—, R¹—C(O)—O—, R¹—S(O)₂—O—, R¹—S(O)_(m)—, H₂N—, R¹—NH—, R¹—N(R¹)—,R¹—C(O)—NH—, R¹—C(O)—N(R⁷¹)—, R¹—S(O)₂—NH—, R¹—S(O)₂—N(R⁷¹)—, R¹—C(O)—,HO—C(O)—, R¹—O—C(O)—, H₂N—C(O)—, R¹—NH—C(O)—, R¹—N(R¹)—C(O)—,H₂N—S(O)₂—, R¹—NH—S(O)₂—, R¹—N(R¹)—S(O)₂—, NC—, O₂N—, phenyl and Het; Yis chosen from the series consisting of N(R¹⁰), S, O, C(R¹²)═C(R¹³),N═C(R¹⁴) and C(R¹⁵)═N; Z is chosen from the series consisting of N andC(R¹⁶); R⁰ is chosen from the series consisting of hydrogen and R²; R¹,R², R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸ are, independently of eachother group R¹, R², R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, chosenfrom the series consisting of (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl- which are all optionally substitutedby one or more identical or different substituents R⁷⁰; R³ and R⁵ areindependently of each other chosen from the series consisting ofhydrogen, (C₁-C₄)-alkyl, phenyl-(C₁-C₄)-alkyl-, phenyl and hydroxy; R⁴and R⁶ are independently of each other chosen from the series consistingof hydrogen and (C₁-C₄)-alkyl; R¹⁰ is chosen from the series consistingof hydrogen and R¹¹; R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently ofeach other chosen from the series consisting of hydrogen, halogen,(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-S(O)_(m)—, H₂N—,(C₁-C₄)-alkyl-NH—, (C₁-C₄)-alkyl-N((C₁-C₄)-alkyl)-, (C₁-C₄)-alkyl-C(O)—,NC— and O₂N—; R²⁰ is chosen from the series consisting of hydrogen and(C₁-C₄)-alkyl; one of the groups R²¹ and R²² is a group of the formulaIIR²⁴—R²³—  II and the other of the groups R²¹ and R²² is chosen from theseries consisting of hydrogen, halogen, R³⁰, HO—, R³⁰—O—, R³⁰—C(O)—O—,R³⁰—S(O)₂—O—, R³⁰—S(O)_(m)—, H₂N—, R³⁰—NH—, R³⁰—N(R³⁰)—, R³⁰—C(O)—NH—,R³⁰—C(O)—N(R⁷¹)—, R³⁰—S(O)₂—NH—, R³⁰—S(O)₂—N(R⁷¹)—, R³⁰—C(O)—, HO—C(O)—,R³⁰—O—C(O)—, H₂N—C(O)—, R³⁰—NH—C(O)—, R³⁰—N(R³⁰)—C(O)—, H₂N—S(O)₂—,R³⁰—NH—S(O)₂—, R³⁰—N(R³⁰)—S(O)₂—, NC—, O₂N— and Het¹; R²³ is a directbond or a chain consisting of 1 to 5 chain members of which 0, 1 or 2chain members are identical or different hetero chain members chosenfrom the series consisting of N(R²⁵), O, S, S(O) and S(O)₂, but twohetero chain members can be present in adjacent positions only if one ofthem is chosen from the series consisting of S(O) and S(O)₂ and theother is chosen from the series consisting of N(R²⁵), O and S, and theother chain members are identical or different groups C(R²⁶)(R²⁶),wherein two adjacent groups C(R²⁶)(R²⁶) can be connected to each otherby a double bond or a triple bond; R²⁴ is chosen from the seriesconsisting of hydrogen, R³¹, HO—, R³¹—O—, R³¹—C(O)—O—, R³¹—S(O)_(m)—,H₂N—, R³¹—NH—, R³¹—N(R³¹)—, R³¹—C(O)—NH—, R³¹—C(O)—N(R⁷¹)—,R³¹—S(O)₂—NH—, R³¹—S(O)₂—N(R⁷¹)—, R³¹—C(O)—, HO—C(O)—, R³¹—O—C(O)—,H₂N—C(O)—, R³¹—NH—C(O)—, R³¹—N(R³¹)—C(O)—, H₂N—S(O)₂—, R³¹—NH—S(O)₂—,R³¹—N(R³¹)—S(O)₂—, NC— and a 3-membered to 10-membered, monocyclic,bicyclic or tricyclic ring which is saturated or unsaturated andcontains 0, 1, 2 or 3 identical or different hetero ring members chosenfrom the series consisting of N,N(R³²), O, S, S(O) and S(O)₂, which ringis optionally substituted on ring carbon atoms by one or more identicalor different substituents chosen from the series consisting of halogen,R³³, HO—, R³³—O—, R³³—O(O)—O—, R³³—S(O)₂—O—, R³³—S(O)_(m)—, H₂N—,R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—, R³³—C(O)—N(R⁷¹)—, R³³—S(O)₂—NH—,R³³—S(O)₂—N(R⁷¹)—, H₂N—S(O)₂—NH—, R³³—NH—S(O)₂—NH—,R³³—N(R³³)—S(O)₂—NH—, H₂N—S(O)₂—N(R⁷¹)—, R³³—NH—S(O)₂—N(R⁷¹)—,R³³—N(R³³)—S(O)₂—N(R⁷¹)—, R³³—C(O)—, HO—C(O)—, R³³—O—C(O)—, H₂N—C(O)—,R³³—NH—C(O)—, R³³—N(R³³)—C(O)—, H₂N—S(O)₂—, R³³—NH—S(O)₂—,R³³—N(R³³)—S(O)₂—, NC—, O₂N—, oxo, phenyl and Het, provided that thetotal number of C, N, O and S atoms which is present in the two groupsR²³ and R²⁴, is at least 5; R²⁵ is chosen from the series consisting ofhydrogen and (C₁-C₄)-alkyl; R²⁶, independently of each other group R²⁶,is chosen from the series consisting of hydrogen, fluorine,(C₁-C₄)-alkyl and HO—, or two groups R²⁶ bonded to the same carbon atomtogether are oxo, or two of the groups R²⁶ or one group R²⁵ and onegroup R²⁶, together with the comprised chain members, form a 3-memberedto 7-membered monocyclic ring which is saturated and contains 0, 1 or 2identical or different hetero ring members chosen from the seriesconsisting of N,N(R³⁴), O, S, S(O) and S(O)₂, which ring is optionallysubstituted on ring carbon atoms by one more identical or differentsubstituents chosen from the series consisting of fluorine and(C₁-C₄)-alkyl; R³¹ is chosen from the series consisting of(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl and (C₂-C₆)-alkynyl which are alloptionally substituted by one or more identical or differentsubstituents R⁷⁰; R³² and R³⁴ are independently of each other chosenfrom the series consisting of hydrogen, R³⁵, R³⁵—S(O)₂—, R³⁵—C(O)—,R³⁵—O—C(O)—, phenyl and Het; R⁵⁰ is chosen from the series consisting ofR⁵¹—O— and R⁵²—N(R⁵³)—; R⁵¹ is chosen from the series consisting ofhydrogen and R⁵⁴; R⁵² is chosen from the series consisting of hydrogen,R⁵⁵, NC— and R⁵⁶—S(O)₂—; R⁵³ is chosen from the series consisting ofhydrogen and R⁵⁷; R⁵⁶ is chosen from the series consisting of R⁵⁸ andphenyl; R⁶⁰, independently of each other group R⁶⁰, is chosen from theseries consisting of hydrogen and (C₁-C₄)-alkyl; R⁷⁰ is chosen from theseries consisting of HO—, R⁷¹—O—, R⁷¹—C(O)—O—, R⁷¹—S(O)_(m)—, H₂N—,R⁷¹—NH—, R⁷¹—N(R⁷¹)—, R⁷¹—C(O)—NH—, R⁷¹—C(O)—N(R⁷¹)—, R⁷¹—S(O)₂—NH—,R⁷¹—S(O)₂—N(R⁷¹)—, HO—C(O)—, R⁷¹—O—C(O)—, H₂N—C(O)—, R⁷¹—NH—C(O)—,R⁷¹—N(R⁷¹)—C(O)—, H₂N—S(O)₂—, R⁷¹—NH—S(O)₂—, R⁷¹—N(R⁷¹)—S(O)₂—, NC—,oxo, phenyl and Het²; R⁷¹, independently of each other group R⁷¹, ischosen from (C₁-C₄)-alkyl, (C₃-C₄)-cycloalkyl and(C₃-C₄)-cycloalkyl-(C₁-C₂)-alkyl-; Het, independently of each othergroup Het, is a monocyclic 4-membered to 7-membered heterocyclic ringwhich comprises 1, 2 or 3 identical or different hetero ring memberschosen from the series consisting of N,N(R⁶⁰), O, S, S(O) and S(O)₂,which ring is saturated or unsaturated and is optionally substituted byone or more identical or different substituents chosen from the seriesconsisting of halogen, (C₁-C₄)-alkyl and R⁷⁰; Het¹ is a monocyclic4-membered to 7-membered heterocyclic ring which comprises 1 or 2identical or different hetero ring members chosen from the seriesconsisting of N,N(R⁶⁰), O, S, S(O) and S(O)₂, which ring is saturatedand is optionally substituted by one or more identical or differentsubstituents chosen from the series consisting of fluorine and(C₁-C₄)-alkyl; Het² is a monocyclic 5-membered or 6-memberedheterocyclic ring which comprises 1, 2 or 3 identical or differenthetero ring members chosen from the series consisting of N,N(R⁶⁰), O andS, which ring is aromatic and is optionally substituted by one or moreidentical or different substituents chosen from the series consisting ofhalogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and NC—; m, independently ofeach other number m, is an integer chosen from the series consisting of0, 1 and 2; phenyl, independently of each other group phenyl, isoptionally substituted by one or more identical or differentsubstituents chosen from the series consisting of halogen,(C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and NC—, unless specified otherwise;cycloalkyl, independently of each other group cycloalkyl, andindependently of any other substituents on cycloalkyl, is optionallysubstituted by one or more identical or different substituents chosenfrom fluorine and (C₁-C₄)-alkyl; and alkyl, alkenyl and alkynyl,independently of each other group alkyl, alkenyl and alkynyl, andindependently of any other substituents on alkyl, alkenyl and alkynyl,is optionally substituted by one or more fluorine substituents; in anyof its stereoisomeric forms or a mixture of stereoisomeric forms in anyratio, or a physiologically acceptable salt thereof, or aphysiologically acceptable solvate of any of them, provided that thecompound of the formula I is not2-[(6,2′,4′-trichlorobiphenyl-3-carbonyl)amino]indane-2-carboxylic acid,2-[6-chloro-[1,1′,4′,1″]terphenyl-3-carbonyl)amino]indane-2-carboxylicacid, 2-(4-chloro-3-phenylethynyl-benzoylamino)-indane-2-carboxylicacid,5-(4-chloro-phenyl)-2-[4-(2-methyl-1H-benzoimidazol-1-ylmethyl)-benzoylamino]-indane-2-carboxylicacid or5-(4-chloro-phenyl)-2-[4-(2-methyl-1H-benzoimidazol-1-ylmethyl)-benzoylamino]-indane-2-carboxylicacid ethyl ester.
 2. The compound according to claim 1, wherein: R³ andR⁵ are independently of each other chosen from the series consisting ofhydrogen, (C₁-C₄)-alkyl, phenyl-(C₁-C₄)-alkyl- and phenyl; in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a physiologically acceptable salt thereof, or a physiologicallyacceptable solvate of any of them.
 3. The compound according to claim 1,wherein: ring A is a cyclohexane ring, a benzene ring, a pyridine ring,a pyridazine ring or a thiophene ring, wherein the cyclohexane ring isoptionally substituted by one or more identical or differentsubstituents chosen from the series consisting of fluorine and(C₁-C₄)-alkyl, and the benzene ring, the pyridine ring, the pyridazinering and the thiophene ring are optionally substituted by one or moreidentical or different substituents chosen from the series consisting ofhalogen, R¹, HO—, R¹—O—, R¹—C(O)—O—, R¹—S(O)₂—O—, R¹—S(O)_(m)—, H₂N—,R¹—NH—, R¹—N(R¹)—, R¹—C(O)—NH—, R¹—C(O)—N(R⁷¹)—, R¹—S(O)₂—NH—,R¹—S(O)₂—N(R⁷¹)—, R¹—C(O)—, HO—C(O)—, R¹—O—C(O)—, H₂N—C(O)—,R¹—NH—C(O)—, R¹—N(R¹)—C(O)—, H₂N—S(O)₂—, R¹—NH—S(O)₂—, R¹—N(R¹)— S(O)₂—,NC— and O₂N—; Y is chosen from the series consisting of S,C(R¹²)═C(R¹³), and C(R¹⁵)═N; and Z is C(R¹⁶); in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a physiologically acceptable salt thereof, or a physiologicallyacceptable solvate of any of them.
 4. The compound according to claim 1,wherein: ring A is a benzene ring, a pyridine ring, a pyrazine or athiophene ring which rings are all optionally substituted by one or twoidentical or different substituents chosen from the series consisting ofhalogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—; Y is chosen from the seriesconsisting of S, C(R¹²)═C(R¹³) and C(R¹⁵)═N; Z is C(R¹⁶); R³ and R⁵ areindependently of each other chosen from the series consisting ofhydrogen and (C₁-C₄)-alkyl; R⁴ and R⁶ are hydrogen; R¹², R¹³, R¹⁵ andR¹⁶ are independently of each other chosen from the series consisting ofhydrogen, halogen (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and NC—; and R²⁰ ishydrogen; in any of its stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof, or a physiologically acceptable solvate of any of them.
 5. Thecompound according to claim 1, wherein: R²¹ is chosen from the seriesconsisting of hydrogen, halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_(m)—, H₂N—, (C₁-C₄)-alkyl-NH—,di((C₁-C₄)-alkyl)N—, (C₁-C₄)-alkyl-C(O)— and NC—; R²² is a group of theformula II;R²⁴—R²³—  II R²³ is a direct bond or a chain consisting of 2, 3 or 4chain members of which 0 or 1 chain members are hetero chain memberschosen from the series consisting of N(R²⁵), O, S, S(O) and S(O)₂, andthe other chain members are identical or different groups C(R²⁶)(R²⁶),wherein two adjacent groups C(R²⁶)(R²⁶) can be connected to each otherby a double bond or a triple bond; in any of its stereoisomeric forms ora mixture of stereoisomeric forms in any ratio, or a physiologicallyacceptable salt thereof, or a physiologically acceptable solvate of anyof them.
 6. The compound according to claim 1, wherein: R²⁴ is a3-membered to 7-membered monocyclic ring or a 7-membered to 10-memberedbicyclic ring, which rings are saturated or unsaturated and contain 0, 1or 2 identical or different hetero ring members chosen from the seriesconsisting of N, N(R³²), O, S, S(O) and S(O)₂, and which rings areoptionally substituted on ring carbon atoms by one or more identical ordifferent substituents chosen from the series consisting of halogen,R³³, HO—, R³³—O—, R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—,R³³—C(O)—NH—, R³³—C(O)—N(R⁷¹)—, R³³—S(O)₂—NH—, R³³—S(O)₂—N(R⁷¹)—,H₂N—S(O)₂—NH—, R³³—NH—S(O)₂—NH—, R³³—N(R³³)—S(O)₂—NH—,H₂N—S(O)₂—N(R⁷¹)—, R³³—NH—S(O)₂—N(R⁷¹)—, R³³—N(R³³)—S(O)₂—N(R⁷¹)—,HO—C(O)—, R³³—O—C(O)—, H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)—, NC—,oxo, phenyl and Het; and R³² is chosen from the series consisting ofhydrogen, R³⁵, R³⁵—C(O)—, R³⁵—O—C(O)— and phenyl; in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a physiologically acceptable salt thereof, or a physiologicallyacceptable solvate of any of them.
 7. The compound according to claim 1,wherein: ring A is a benzene ring, a pyridine ring, a pyrazine or athiophene ring which rings are all optionally substituted by one or twoidentical or different substituents chosen from the series consisting ofhalogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—; Y is chosen from the seriesconsisting of S, C(R¹²)═C(R¹³) and C(R¹⁵)═N; Z is C(R¹⁶); R³ and R⁵ areindependently of each other chosen from the series consisting ofhydrogen and (C₁-C₄)-alkyl; R⁴ and R⁶ are hydrogen; R¹², R¹³, R¹⁵ andR¹⁶ are independently of each other chosen from the series consisting ofhydrogen, halogen (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and NC—; R²⁰ ishydrogen; R²¹ is chosen from the series consisting of hydrogen, halogen,(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)_(m)—, H₂N—, (C₁-C₄)-alkyl-NH—, di((C₁-C₄)-alkyl)N—,(C₁-C₄)-alkyl-C(O)— and NC—; R²² is a group of the formula II;R²⁴—R²³—  II R²³ is a direct bond or a chain consisting of 2, 3 or 4chain members of which 0 or 1 chain members are hetero chain memberschosen from the series consisting of N(R²⁵), O, S, S(O) and S(O)₂, andthe other chain members are identical or different groups C(R²⁶)(R²⁶),wherein two adjacent groups C(R²⁶)(R²⁶) can be connected to each otherby a double bond or a triple bond; R²⁴ is a 3-membered to 7-memberedmonocyclic ring or a 7-membered to 10-membered bicyclic ring, whichrings are saturated or unsaturated and contains 0, 1 or 2 identical ordifferent hetero ring members chosen from the series consisting of N,N(R³²), O, S, S(O) and S(O)₂, which ring is optionally substituted onring carbon atoms by one or more identical or different substituentschosen from the series consisting of halogen, R³³, HO—, R³³—O—,R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—,R³³—C(O)—N(R⁷¹)—, R³³—S(O)₂—NH—, R³³—S(O)₂—N(R⁷¹)—, HO—C(O)—,R³³—O—C(O)—, H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)—, NC—, oxo, phenyland Het; and R³² is chosen from the series consisting of hydrogen, R³⁵,R³⁵—C(O)—, R³⁵—O—C(O)— and phenyl; in any of its stereoisomeric forms ora mixture of stereoisomeric forms in any ratio, or a physiologicallyacceptable salt thereof, or a physiologically acceptable solvate of anyof them.
 8. The compound according to claim 1, wherein ring A is abenzene ring which is optionally substituted by one or two identical ordifferent substituents chosen from the series consisting of halogen,(C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—; Y is C(R¹²)═C(R¹³); Z is C(R¹⁶); R³,R⁴, R⁵ and R⁶ are hydrogen; R¹², R¹³ and R¹⁶ are independently of eachother chosen from the series consisting of hydrogen, halogen,(C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and NC—; R²⁰ is hydrogen; R²¹ is chosenfrom the series consisting of hydrogen, halogen, (C₁-C₄)-alkyl,HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_(m)—,(C₁-C₄)-alkyl-C(O)— and NC—; R²² is a group of the formula II;R²⁴—R²³—  II R²³ is a direct bond or a chain consisting of 2, 3 or 4chain members of which 0 or 1 chain members are hetero chain memberschosen from the series consisting of N(R²⁵), O, S, S(O) and S(O)₂, andthe other chain members are identical or different groups C(R²⁶)(R²⁶);R²⁴ is a benzene ring which is optionally substituted by one or moreidentical or different substituents chosen from the series consisting ofhalogen, R³³, HO—, R³³—O—, R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—,R³³—C(O)—NH—, R³³—S(O)₂—NH—, HO—C(O)—, R³³—O—C(O)—, H₂N—C(O)—,R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—; provided that the total numberof C, N, O and S atoms which is present in the two groups R²³ and R²⁴,is at least 5; R²⁵ is chosen from the series consisting of hydrogen and(C₁-C₄)-alkyl; R²⁶, independently of each other group R²⁶, is chosenfrom the series consisting of hydrogen, fluorine, (C₁-C₄)-alkyl and HO—,or two of the groups R²⁶ which are bonded to the same carbon atom in thechain, together with the carbon atom carrying them, form a cyclopropanering; R³³ is, independently of each other group R³³, chosen from theseries consisting of (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, which are all optionally substitutedby one or more identical or different substituents R⁷⁰; R⁵⁰ is chosenfrom the series consisting of R⁵¹—O— and R⁵²—N(R⁵³)—; R⁵¹ is chosen fromthe series consisting of hydrogen and (C₁-C₄)-alkyl; R⁵² is chosen fromthe series consisting of hydrogen and (C₁-C₄)-alkyl; R⁵³ is chosen fromthe series consisting of hydrogen and (C₁-C₄)-alkyl; R⁷⁰ is chosen fromthe series consisting of HO— and R⁷¹—O—; R⁷¹ is (C₁-C₄)-alkyl; m,independently of each other number m, is an integer chosen from theseries consisting of 0 and 2; cycloalkyl, independently of each othergroup cycloalkyl, and independently of any other substituents oncycloalkyl, is optionally substituted by one or more identical ordifferent substituents chosen from fluorine and (C₁-C₄)-alkyl; andalkyl, independently of each other group alkyl, and independently of anyother substituents on alkyl, is optionally substituted by one or morefluorine substituents; in any of its stereoisomeric forms or a mixtureof stereoisomeric forms in any ratio, or a physiologically acceptablesalt thereof, or a physiologically acceptable solvate of any of them. 9.The compound according to claim 1, which is2-[4-methylsulfanyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid, 2-[4-acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid, 2-[4-ethyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid, 2-[4-ethoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid,2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid,2-{4-methoxy-3-[2-(3-trifluoromethylsulfanyl-phenyl)-ethoxy]-benzoylamino}-indane-2-carboxylicacid,2-[4-methoxy-3-(1-m-tolyl-cyclopropylmethoxy)-benzoylamino]-indane-2-carboxylicacid,2-{3-[2-(3-cyano-phenyl)-ethoxy]-4-methoxy-benzoylamino}-indane-2-carboxylicacid,5-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylicacid,2-{[5-acetyl-4-(2-m-tolyl-ethoxy)-thiophene-2-carbonyl]-amino}-indane-2-carboxylicacid,2-[3-fluoro-4-methoxy-5-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid,2-[4-methoxy-3-(2-m-tolyloxy-ethyl)-benzoylamino]-indane-2-carboxylicacid,2-[4-methoxy-3-(3-m-tolyl-propyl)-benzoylamino]-indane-2-carboxylicacid,5-fluoro-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid,2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-5,6-dimethyl-indane-2-carboxylicacid, 2-[4-cyano-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylicacid,2-[4-methoxy-3-(2-m-tolyl-ethylamino)-benzoylamino]-indane-2-carboxylicacid,2-{3-[2-(3-chloro-phenyl)-ethoxy]-4-methyl-benzoylamino}-indane-2-carboxylicacid,2-[4-methoxy-3-(2-m-tolyl-ethylsulfanyl)-benzoylamino]-indane-2-carboxylicacid,2-[3-(2-m-tolyl-ethoxy)-4-trifluoromethyl-benzoylamino]-indane-2-carboxylicacid,2-{3-[2-(2-fluoro-5-methyl-phenyl)-ethoxy]-4-trifluoromethyl-benzoylamino}-indane-2-carboxylicacid,2-(3-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylicacid,2-{[6-methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-indane-2-carboxylicacid,2-[(3′-methanesulfonylamino-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylicacid,2-[(3′-dimethylaminosulfonylamino-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylicacid,2-[(6-methoxy-6-trifluoromethoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylicacid,2-[(3′-cyanomethyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylicacid,2-[(3′-isopropyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylicacid,2-[(3′-chloro-6-methoxy-2′-methyl-biphenyl-3-carbonyl)-amino]-indane-2-carboxylicacid,2-{[5-(3-chloro-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-indane-2-carboxylicacid, or2-[3-(2,2-difluoro-2-phenyl-ethoxy)-4-methoxy-benzoylamino]-indane-2-carboxylicacid; in any of its stereoisomeric forms or a mixture of stereoisomericforms in any ratio, or a physiologically acceptable salt thereof, or aphysiologically acceptable solvate of any of them.
 10. A process for thecompound according to claim 1, comprising reacting a compound of formulaIII with a compound of the formula IV,

wherein the ring A and the groups Y, Z, R³ to R⁶, R²⁰ to R²² and R⁵⁰ inthe compounds of the formulae III and IV are defined as in claim 1 andadditionally functional groups can be present in protected form or inthe form of a precursor group, and the group G in the compound of theformula IV is HO—, (C₁-C₄)-alkyl-O— or halogen.
 11. A pharmaceuticalcomposition comprising the compound according to claim 1, in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a physiologically acceptable salt thereof, or a physiologicallyacceptable solvate of any of them, and a pharmaceutically acceptablecarrier.
 12. A pharmaceutical composition comprising the compoundaccording to claim 9, in any of its stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof, or a physiologically acceptable solvate of any of them, and apharmaceutically acceptable carrier.
 13. A method for treating acardiovascular disease, heart failure, cardiomyopathy, myocardialinfarction, myocardial remodeling, vascular remodeling, hypertension,atherosclerosis, peripheral arterial occlusive disease, restenosis,thrombosis, vascular permeability disorder, an inflammatory disease,rheumatoid arthritis, osteoarthritis, renal disease, renal papillarynecrosis, renal failure, a pulmonary disease, chronic obstructivepulmonary disease, asthma, acute respiratory dystress syndrome, animmunological disease, an allergic disease, tumor growth, metastasis, ametabolic disease, a fibrotic disease, pulmonary fibrosis, cardiacfibrosis, vascular fibrosis, perivascular fibrosis, renal fibrosis,liver fibrosis, fibrosing skin condition, psoriasis, pain, pruritus,retinal ischemia, reperfusion damage, macular degeneration, apsychiatric disorder, a neurodegenerative disease, a cerebral nervedisorder, a peripheral nerve disorder, an endocrinic disorder,hyperthyroidism, a scarring disorder or a would healing disorder, or forcardioprotection or renoprotection, in a patient in need thereof,comprising administering to the patient a pharmaceutically effectiveamount of the compound according to claim 1, in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a physiologically acceptable salt thereof, or a physiologicallyacceptable solvate of any of them.
 14. A method for treating acardiovascular disease, heart failure, cardiomyopathy, myocardialinfarction, myocardial remodeling, vascular remodeling, hypertension,atherosclerosis, peripheral arterial occlusive disease, restenosis,thrombosis, vascular permeability disorder, an inflammatory disease,rheumatoid arthritis, osteoarthritis, renal disease, renal papillarynecrosis, renal failure, a pulmonary disease, chronic obstructivepulmonary disease, asthma, acute respiratory dystress syndrome, animmunological disease, an allergic disease, tumor growth, metastasis, ametabolic disease, a fibrotic disease, pulmonary fibrosis, cardiacfibrosis, vascular fibrosis, perivascular fibrosis, renal fibrosis,liver fibrosis, fibrosing skin condition, psoriasis, pain, pruritus,retinal ischemia, reperfusion damage, macular degeneration, apsychiatric disorder, a neurodegenerative disease, a cerebral nervedisorder, a peripheral nerve disorder, an endocrinic disorder,hyperthyroidism, a scarring disorder or a would healing disorder, or forcardioprotection or renoprotection, in a patient in need thereof,comprising administering to the patient a pharmaceutically effectiveamount of the compound according to claim 9, in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a physiologically acceptable salt thereof, or a physiologicallyacceptable solvate of any of them.